3-phosphoglycerate dehydrogenase inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/150,669, filed Jan. 15, 2021, which is a continuation of U.S.application Ser. No. 16/082,659, filed Sep. 6, 2018, now U.S. Pat. No.10,954,220, which is a national stage application of InternationalPatent Application No. PCT/US2017/021420, filed Mar. 8, 2017, whichclaims the benefit of U.S. Provisional Application No. 62/305,930, filedMar. 9, 2016, the disclosures of which are hereby incorporated byreference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibiting 3-phosphoglycerate dehydrogenase. The invention also providespharmaceutically acceptable compositions comprising compounds of thepresent invention and methods of using said compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in thebiosynthesis of L-serine, which is the conversion of 3-phosphoglycerateinto 3-phosphohydroxypyruvate with a reduction of nicotinamide adeninedinucleotide (NADY) to NADH.

Certain cancers, including human melanomas and breast cancers, can havehigh levels of PHGDH. These cancer cells are dependent on PHGDH fortheir growth and survival as PHGDH catalyzes serine production and mayalso be a significant source of NADPH in cancer cells. Targeting PHGDHby small molecule inhibitors could be a therapeutic strategy to reducecancer cell growth and survival. Accordingly, there remains a need tofind PHGDH inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective as PHGDHinhibitors. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, X, L¹, Y¹ and Y² is as defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with PHGDH. Such diseases,disorders, or conditions include cellular proliferative disorders (e.g.,cancer) such as those described herein.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of CertainAspects of the Invention

Compounds of the present invention, and compositions thereof, are usefulas inhibitors of PHGDH. Without wishing to be bound by any particulartheory, it is believed that compounds of the present invention, andcompositions thereof, may inhibit the activity of PHGDH and/or inhibitthe production of NADPH, and thus reduce the growth of cells inproliferative disorders such as cancer.

In certain embodiments, the present invention provides a compound offormula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is hydrogen or C₁₋₄ alkyl;    -   each of R² and R³ is independently halogen, —OR, —CN, C₁₋₆        aliphatic optionally substituted with 1, 2, or 3 halogens, or        -L-R′; or R² and R³ are optionally taken together with the        carbon atoms to which they are attached and any intervening        atoms to form a 5-8 membered partially unsaturated ring having        0-2 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   R⁴ is hydrogen, halogen, —OR⁵, —CN, C₁₋₆ aliphatic optionally        substituted with 1, 2, or 3 halogens, or -L-R′;    -   each R is independently hydrogen or an optionally substituted        group selected from C₁₋₆ aliphatic, a 3-8 membered saturated or        partially unsaturated monocyclic carbocyclic ring, phenyl, an        8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered        saturated or partially unsaturated monocyclic heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic        ring having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   R⁵ is hydrogen, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-Cy′, or C₁₋₆ alkyl        optionally substituted with 1, 2, or 3 halogens;    -   each L is independently a C₁₋₆ bivalent straight or branched        hydrocarbon chain wherein 1-4 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—,        —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO₂—;    -   each R′ is independently hydrogen, C₁₋₆ aliphatic, or an        optionally substituted 4-8 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   R⁶ is hydrogen or C₁₋₄ alkyl;    -   R⁷ is hydrogen, —CO₂R, optionally substituted C₁₋₆ aliphatic,        -Cy-, or a bivalent 3-7 membered ring;    -   L¹ is a covalent bond or a C₁₋₁₀ bivalent straight or branched        hydrocarbon chain wherein 1-5 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,        —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,        —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—,        —(R)NC(S)N(R)—, or -Cy-;    -   each -Cy- is independently a bivalent 6-membered arylene ring        containing 0-2 nitrogen atoms, or a bivalent 5-membered        heteroarylene ring with 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or a bivalent partially        unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, wherein -Cy- is optionally substituted with 1 or 2        substituents independently selected from C₁₋₄ alkyl or —OR;    -   Cy′ is a 4-8 membered saturated or partially unsaturated        monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur,    -   R⁸ is hydrogen, —CO₂R, or C₁₋₆ optionally substituted aliphatic;    -   R⁹ is hydrogen, halogen, C₁₋₄ alkyl, —CN, —OR, —(CH₂)_(n)—        (optionally substituted phenyl), or L²-R′;    -   each L² is independently C₁₋₈ bivalent straight or branched        hydrocarbon chain wherein 1-4 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,        —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,        —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or        —(R)NC(S)N(R)—;    -   R¹⁰ is C₁₋₆ aliphatic optionally substituted with 1, 2, or 3        halogens, —C(O)CH₃, or —SO₂—N(R¹)(R¹¹);    -   R¹¹ is —C(O)CH₃, —C(O)NHR¹, or pyrazinyl;    -   n is independently 0, 1, 2, 3, 4, or 5;    -   m is independently 0, 1, or 2;    -   X is O, S, or —N(R¹⁰)—; and    -   each of Y¹ and Y² is independently ═N— or ═C(R⁴)—.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3 (4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR^(o)₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o), —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; —SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R; wherein each R isindependently hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, R¹, of a provided compound comprises oneor more deuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits PHGDH with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 100 μM, less than about 50 μM, less than about 1 μM, lessthan about 500 nM, less than about 100 nM, less than about 10 nM, orless than about 1 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in PHGDH activity between a samplecomprising a compound of the present invention, or composition thereof,and PHGDH, and an equivalent sample comprising PHGDH, in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

In certain embodiments, the present invention provides a compound offormula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is hydrogen or C₁₋₄ alkyl;    -   each of R² and R³ is independently halogen, —OR, —CN, C₁₋₆        aliphatic optionally substituted with 1, 2, or 3 halogens, or        -L-R′; or R² and R³ are optionally taken together with the        carbon atoms to which they are attached and any intervening        atoms to form a 5-8 membered partially unsaturated ring having        0-2 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   R⁴ is hydrogen, halogen, —OR⁵, —CN, C₁₋₆ aliphatic optionally        substituted with 1, 2, or 3 halogens, or -L-R′;    -   each R is independently hydrogen or an optionally substituted        group selected from C₁₋₆ aliphatic, a 3-8 membered saturated or        partially unsaturated monocyclic carbocyclic ring, phenyl, an        8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered        saturated or partially unsaturated monocyclic heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic        ring having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   R⁵ is hydrogen, —(CH₂)_(n)-phenyl, —(CH₂)_(n)-Cy′, or C₁₋₆ alkyl        optionally substituted with 1, 2, or 3 halogens;    -   each L is independently a C₁₋₆ bivalent straight or branched        hydrocarbon chain wherein 1-4 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—,        —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO₂—;    -   each R′ is independently hydrogen, C₁₋₆ aliphatic, or an        optionally substituted 4-8 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   R⁶ is hydrogen or C₁₋₄ alkyl;    -   R⁷ is hydrogen, —CO₂R, optionally substituted C₁₋₆ aliphatic,        -Cy-, or a bivalent 3-7 membered ring;    -   L¹ is a covalent bond or a C₁₋₈ bivalent straight or branched        hydrocarbon chain wherein 1-5 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,        —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,        —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—,        —(R)NC(S)N(R)—, or -Cy-;    -   each -Cy- is independently a bivalent 6-membered arylene ring        containing 0-2 nitrogen atoms, or a bivalent 5-membered        heteroarylene ring with 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or a bivalent partially        unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, wherein -Cy- is optionally substituted with 1 or 2        substituents independently selected from C₁₋₄ alkyl or —OR;    -   -Cy′ is a 4-8 membered saturated or partially unsaturated        monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur,    -   R⁸ is hydrogen, —CO₂R, or C₁₋₆ optionally substituted aliphatic;    -   R⁹ is hydrogen, halogen, C₁₋₄ alkyl, —CN, —OR, —(CH₂)_(n)—        (optionally substituted phenyl), or L²-R′;    -   each L² is independently C₁₋₈ bivalent straight or branched        hydrocarbon chain wherein 1-4 methylene units of the chain are        independently and optionally replaced with —O—, —C(O)—, —C(O)O—,        —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,        —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,        —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or        —(R)NC(S)N(R)—;    -   R¹⁰ is C₁₋₆ aliphatic optionally substituted with 1, 2, or 3        halogens, —C(O)CH₃, or —SO₂—N(R¹)(R¹¹);    -   R¹¹ is —C(O)CH₃, —C(O)NHR¹, or pyrazinyl;    -   n is independently 0, 1, 2, 3, 4, or 5;    -   m is independently 0, 1, or 2;    -   X is O, S, or —N(R¹⁰)—; and    -   each of Y¹ and Y² is independently ═N— or ═C(R⁴)—.

As defined above and described herein, R¹ is hydrogen or C₁₋₄ alkyl. Insome embodiments, R¹ is hydrogen. In some embodiments, R¹ is C₁₋₄ alkyl.In some embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, R² is independently halogen, —OR,—CN, C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 halogens, or-L-R′; or R² and R³ are optionally taken together with the carbon atomsto which they are attached and any intervening atoms to form a 5-8membered partially unsaturated ring having 0-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is halogen. In some embodiments, R² is —OR. Insome embodiments, R² is —CN. In some embodiments, R² is C₁₋₆ aliphaticoptionally substituted with 1, 2, or 3, halogens. In some embodiments,R² is -L-R′. In some embodiments, R² and R³ are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a 5-8 membered partially unsaturated ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is F, Cl, —CF₃, —OCF₃, —OCHF₂, —OCH₂Ph, —OCH₃,—CN, —CH₃,

embodiments, R² is F or Cl. In some embodiments, R² is —OCH₃. In someembodiments, R² is —CH₃.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined above and described herein, R³ is independently halogen, —OR,—CN, C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 halogens, or-L-R′; or R² and R³ are optionally taken together with the carbon atomsto which they are attached and any intervening atoms to form a 5-8membered partially unsaturated ring having 0-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R³ is halogen. In some embodiments, R³ is —OR. Insome embodiments, R³ is —CN. In some embodiments, R³ is C₁₋₆ aliphaticoptionally substituted with 1, 2, or 3, halogens. In some embodiments,R³ is -L-R′. In some embodiments, R² and R³ are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a 5-8 membered partially unsaturated ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R³ is F, Cl, —CF₃, —OCF₃, —OCHF₂, —OCH₂Ph, —OCH₃,—CN, —CH₃,

In some embodiments, R³ is F or Cl. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is —CH₃.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, R⁴ is hydrogen, halogen, —OR⁵,—CN, C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 halogens, or-L-R′.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is halogen.In some embodiments, R⁴ is —OR⁵. In some embodiments, R⁴ is C₁₋₆aliphatic optionally substituted with 1, 2, or 3 halogens. In someembodiments, R⁴ is -L-R′.

In some embodiments, R⁴ is F, Cl, —CF₃, —OCF₃, —OCHF₂, —OCH₂Ph, —OCH₃,—CN, —CH₃,

In some embodiments, R⁴ is F or Cl. In some embodiments, R⁴ is —OCH₃. Insome embodiments, R⁴ is —CH₃.

In some embodiments, R⁴ is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic, a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted C₁₋₆ aliphatic group. In some embodiments, R isan optionally substituted 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 8-10 membered bicyclic aromatic carbocyclic ring. In someembodiments, R is an optionally substituted 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R is a 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R is an optionally substituted 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each L is independently a C₁₋₆bivalent straight or branched hydrocarbon chain wherein 1-4 methyleneunits of the chain are independently and optionally replaced with —O—,—C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —C(O)N(R)—,—(R)NC(O)—, —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO₂—.

In some embodiments, L is a C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1-4 methylene units of the chain areindependently replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—, —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—,or —SO₂—. In some embodiments, 1 or 2 methylene units of the chain arereplaced with —O—. In some embodiments, 1 or 2 methylene units of thechain are replaced with —C(O)—. In some embodiments, 1 or 2 methyleneunits of the chain are replaced with —C(O)O—. In some embodiments, 1 or2 methylene units of the chain are replaced with —OC(O)—. In someembodiments, 1 or 2 methylene units of the chain are replaced with—OC(O)N(R)—. In some embodiments, 1 or 2 methylene units of the chainare replaced with —(R)NC(O)O—. In some embodiments, 1 or 2 methyleneunits are replaced with —C(O)N(R)—. In some embodiments, 1 or 2methylene units of the chain are replaced with —(R)NC(O)—. In someembodiments, 1 or 2 methylene units of the chain are replaced with—N(R)—. In some embodiments, 1 or 2 methylene units of the chain arereplaced with —N(R)C(O)N(R)—. In some embodiments, 1 or 2 methyleneunits of the chain are replaced with —S—. In some embodiments, 1 or 2methylene units of the chain are replaced with —SO—. In someembodiments, 1 or 2 methylene units are replaced with —SO₂—. In someembodiments, 1 or 2 methylene units of the chain are independentlyreplaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—,—C(O)N(R)—, —(R)NC(O)—, —N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO₂—,wherein each R is independently hydrogen or methyl.

In some embodiments, L is a C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—, —N(R)—, or —N(R)C(O)N(R)—, whereinR is hydrogen or methyl. In some embodiments, L is a C₁₋₆ bivalentstraight or branched hydrocarbon chain wherein 1 or 2 methylene units ofthe chain are independently replaced with —O—, —C(O)—, —C(O)N(R)—,—(R)NC(O)—, or —N(R)—, wherein each R is independently hydrogen ormethyl.

In some embodiments, L is —O—. In some embodiments, L is —O—CH₂—. Insome embodiments, L is —O—CH₂—CH₂—. In some embodiments, L is—O—CH₂—CH₂—O—.

In some embodiments, L is selected from those depicted in Table 1,below.

As defined above and described herein, each R′ is independentlyhydrogen, C₁₋₆ aliphatic, or an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R′ is hydrogen. In some embodiments, R′ is C₁₋₆aliphatic. In some embodiments, R′ is an optionally substituted 4-8membered saturated or partially saturated monocyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, R′ is

In some embodiments, R′ is

In some embodiments, R′ is

In some embodiments, R′ is

In some embodiments, R′ is selected from those depicted in Table 1,below.

As defined above and described herein, R⁵ is hydrogen,—(CH₂)_(n)-phenyl, —(CH₂)_(n)-Cy′, or C₁₋₆ alkyl optionally substitutedwith 1, 2, or 3 halogens;

In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is—(CH₂)_(n)-phenyl. In some embodiments, R⁵ is C₁₋₆ alkyl optionallysubstituted with 1, 2, or 3 halogens.

In some embodiments, R⁵ is hydrogen, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃,—CH₂CHF₂, —CH₂CF₃, or

In some embodiments, R⁵ is selected from those depicted in Table 1,below.

As defined above, and described herein, R⁶ is hydrogen or C₁₋₄ alkyl. Insome embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is C₁₋₄ alkyl.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above, and described herein, R⁷ is hydrogen, —CO₂R,optionally substituted C₁₋₆ aliphatic, -Cy-, or a bivalent 3-7 memberedring.

In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ is —CO₂R.In some embodiments, R⁷ is C₁₋₆ aliphatic. In some embodiments, R⁷ is-Cy. In some embodiments, R⁷ is a bivalent 3-7 membered ring.

In some embodiments, R⁷ is hydrogen, methyl, ethyl, cyclopropyl,cyclobutyl, tetrazolyl, or —CO₂H.

In some embodiments R⁷ is selected from those depicted in Table 1,below.

As defined above, and described herein, L¹ is a covalent bond or a C₁₋₈bivalent straight or branched hydrocarbon chain wherein 1-5 methyleneunits of the chain are independently and optionally replaced with —O—,—C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—,—C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, —(R)NC(S)N(R)—, or-Cy-.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₈ bivalent straight or branched hydrocarbon chain. In someembodiments, L¹ is a C₁₋₈ bivalent straight or branched hydrocarbonchain wherein 1-5 methylene units of the chain are independentlyreplaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—,—(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—,—SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—,—(R)NC(S)N(R)—, or -Cy-. In some embodiments, 1, 2, or 3 methylene unitsof the chain are replaced with —O—. In some embodiments, 1, 2, or 3methylene units of the chain are replaced with —C(O)—. In someembodiments, 1, 2, or 3 methylene units of the chain are replaced with—C(O)O— or —OC(O)—. In some embodiments, 1, 2, or 3 methylene units ofthe chain are replaced with —N(R)—. In some embodiments, 1, 2, or 3methylene units of the chain are replaced with —C(O)N(R)— or —(R)NC(O)—.In some embodiments, 1, 2, or 3 methylene units of the chain arereplaced with —OC(O)N(R)— or —(R)NC(O)O—. In some embodiments, 1, 2, or3 methylene units of the chain are replaced with —N(R)C(O)N(R)—. In someembodiments, 1, 2, or 3 methylene units of the chain are replaced with—S—. In some embodiments, 1, 2, or 3 methylene units of the chain arereplaced with —SO—. In some embodiments, 1, 2, or 3 methylene units ofthe chain are replaced with —SO₂—. In some embodiments, 1, 2, or 3methylene units of the chain are replaced with —SO₂N(R)— or —(R)NSO₂—.In some embodiments, 1, 2, or 3 methylene units of the chain arereplaced with —C(S)—. In some embodiments, 1, 2, or 3 methylene units ofthe chain are replaced with —C(S)O— or —OC(S)—. In some embodiments, 1,2, or 3 methylene units of the chain are replaced with —C(S)N(R)— or—(R)NC(S)—. In some embodiments, 1, 2, or 3 methylene units of the chainare replaced with —(R)NC(S)N(R)—. In some embodiments, 1, 2, or 3methylene units of the chain are replaced with -Cy-. In someembodiments, L¹ is a C₁₋₆ bivalent straight or branched hydrocarbonchain wherein 1, 2, or 3 methylene units of the chain are independentlyand optionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—,—C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—,—SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,—(R)NC(S)—, —(R)NC(S)N(R)—, or -Cy-, wherein each R is independentlyhydrogen, —CH₂-phenyl, phenyl, —CH₃, —CH₂CH₃, cyclopentyl, cyclohexyl,—CH₂F, —CHF₂, —CF₃, —CH₂CHF₂, or —CH₂CF₃; or each R is independentlyhydrogen or methyl; or R is hydrogen.

In some embodiments, L¹ is a C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, 3, or 4 methylene units of the chain areindependently and optionally replaced with —O—, —C(O)—, —C(O)O—,—OC(O)—, —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —SO₂—, or -Cy-.

In some embodiments, L¹ is a C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —NH—,—C(O)NH—, —NHC(O)—, —NHC(O)NH—, —SO₂—, or -Cy-.

In some embodiments, L¹ is a C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently replaced with —C(O)—, —NH—, —C(O)NH—, —NHC(O)—,—NHC(O)NH—, —SO₂—, or -Cy-.

In some embodiments, L¹ is a C₃₋₆ bivalent straight or branchedhydrocarbon chain wherein 2 or 3 methylene units of the chain areindependently replaced with —SO₂—, —SO₂NH—, —C(O)O—, —C(O)NH—, or—NHC(O)NH—. In some embodiments, L¹ is a C₃₋₆ bivalent branchedhydrocarbon chain wherein 2 or 3 methylene units of the chain areindependently replaced with —SO₂—, —SO₂NH—, —C(O)O—, —C(O)NH—, or—NHC(O)NH—.

In some embodiments, the methylene unit of L¹ is replaced with —SO₂—. Insome embodiments, the methylene unit of L¹ is replaced with —SO₂NH—. Insome embodiments, the methylene unit of L¹ is substituted with twomethyl groups. In some embodiments, the methylene unit of L¹ is replacedwith —C(O)NH—. In some embodiments, the methylene unit of L¹ is replacedwith —SO₂— and the adjacent methylene unit is replaced with —NHC(O)NH—.In some embodiments, the methylene unit of L¹ is substituted with twomethyl groups and the adjacent methylene unit is replaced with—NHC(O)NH—.

In some embodiments, L¹ is a covalent bond.

In some embodiments, L¹ is —SO₂NH—. In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each -Cy- is independently abivalent 6-membered arylene ring containing 0-2 nitrogen atoms whereinthe ring is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkyl or —OR, or a bivalent 5-memberedheteroarylene ring with 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10membered bicyclic heterocyclene ring with 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is a bivalent 6-membered arylene ringcontaining 0-2 nitrogen atoms. In some embodiments, -Cy- is a bivalent6-membered arylene ring containing 0-2 nitrogen atoms wherein the ringis substituted with 1 or 2 substituents independently selected from C₁₋₄alkyl or —OR, wherein R is hydrogen or C₁₋₄ alkyl. In some embodiments,-Cy- is a bivalent 5-membered heteroarylene ring with 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, -Cy- is a bivalent partially unsaturated 8-10 memberedbicyclic heterocyclene ring with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

In some embodiments, -Cy- is selected from those depicted in Table 1,below.

As defined above and described herein, R¹⁰ is C₁₋₆ aliphatic optionallysubstituted with 1, 2, or 3 halogens, —C(O)CH₃, or —SO₂—N(R¹)(R¹¹). Insome embodiments, R¹⁰ is C₁₋₆ aliphatic optionally substituted with 1,2, or 3 halogens. In some embodiments, R¹⁰ is methyl. In someembodiments, R¹⁰ is ethyl. In some embodiments, R¹⁰ is —CH₂CF₃. In someembodiments, R¹⁰ is —C(O)CH₃. In some embodiments, R¹⁰ is—SO₂—N(R¹)(R¹¹).

In some embodiments, R¹⁰ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹¹ is —C(O)CH₃, —C(O)NHR¹, orpyrazinyl;

In some embodiments, R¹¹ is —C(O)CH₃. In some embodiments, R¹¹ is—C(O)NHR¹. In some embodiments R¹¹ is pyrazinyl.

In some embodiments, R¹¹ is selected from those depicted in Table 1,below.

As defined above and described herein, X is O, S, or —N(R¹⁰)—.

In some embodiments, X is 0. Is some embodiments, X is S. In someembodiments X is —N(R¹⁰)—.

In some embodiments, X is selected from those depicted in Table 1,below.

As defined above and described herein, each of Y¹ and Y² isindependently ═N— or ═C(R⁴)—. In some embodiments, Y¹ is N and Y² is═(CH)—. In some embodiments Y¹ is ═(CH)— and Y² is N.

In some embodiments, the present invention provides a compound ofFormulae II-a, II-b, II-c, II-d, or II-e:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R¹, R⁹, R¹⁰, R¹¹, R, R′, L¹, -Cy-, Y¹, Y², and n isdefined above and described in embodiments herein.

In some embodiments, the present invention provides a compound ofFormulae III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, orIII-i:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R, R⁹, R¹⁰, R¹¹, R, R′, L¹, -Cy-, Y¹, Y², and n isdefined above and described in embodiments herein.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

In certain embodiments, the present invention provides any compounddepicted in Table 1, above, or a pharmaceutically acceptable saltthereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit PHGDH, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably inhibit PHGDH, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition. In some embodiments, a composition of thisinvention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof PHGDH, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of PHGDH or a mutant thereof.

The activity of a compound utilized in this invention as an inhibitor ofPHGDH, or a mutant thereof, may be assayed in vitro, in vivo or in acell line. In vitro assays include assays that determine inhibition ofPHGDH, or a mutant thereof. Alternate in vitro assays quantitate theability of the inhibitor to bind to PHGDH. Detailed conditions forassaying a compound utilized in this invention as an inhibitor of PHGDH,or a mutant thereof, are set forth in the Examples below.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of PHGDH and are therefore useful fortreating one or more disorders associated with activity of PHGDH. Thus,in certain embodiments, the present invention provides a method fortreating a PHGDH-mediated disorder comprising the step of administeringto a patient in need thereof a compound of the present invention, orpharmaceutically acceptable composition thereof.

As used herein, the terms “PHGDH-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which PHGDH, or a mutant thereof, is known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichPHGDH, or a mutant thereof, are known to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition includes, but is not limited to, acellular proliferative disorder.

Cellular Proliferative Disorders

The present invention features methods and compositions for thediagnosis and prognosis of cellular proliferative disorders (e.g.,cancer) and the treatment of these disorders by targeting PHGDH of theserine biosynthetic pathway. Cellular proliferative disorders describedherein include, e.g., cancer, obesity, and proliferation-dependentdiseases. Such disorders may be diagnosed using methods known in theart.

Cancer

Cancer includes, in one embodiment, without limitation, leukemias (e.g.,acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia,acute myeloblastic leukemia, acute promyelocytic leukemia, acutemyelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,meningioma, melanoma, neuroblastoma, and retinoblastoma). In someembodiments, the cancer is melanoma or breast cancer.

Cancers includes, in another embodiment, without limitation,mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, gastrointestinal (gastric,colorectal, and duodenal), uterine cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, testicular cancer,chronic or acute leukemia, chronic myeloid leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, non-Hodgkin's lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma,fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one ormore of the foregoing cancers.

In some embodiments, the present invention provides a method fortreating a tumor in a patient in need thereof, comprising administeringto the patient any of the compounds, salts or pharmaceuticalcompositions described herein. In some embodiments, the tumor comprisesany of the cancers described herein. In some embodiments, the tumorcomprises melanoma cancer. In some embodiments, the tumor comprisesbreast cancer. In some embodiments, the tumor comprises lung cancer. Insome embodiments the tumor comprises small cell lung cancer (SCLC). Insome embodiments the tumor comprises non-small cell lung cancer (NSCLC).

In some embodiments, the tumor is treated by arresting further growth ofthe tumor. In some embodiments, the tumor is treated by reducing thesize (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%,75%, 90% or 99% relative to the size of the tumor prior to treatment. Insome embodiments, tumors are treated by reducing the quantity of thetumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99%relative to the quantity of tumors prior to treatment.

Other Proliferative Diseases

Other proliferative diseases include, e.g., obesity, benign prostatichyperplasia, psoriasis, abnormal keratinization, lymphoproliferativedisorders (e.g., a disorder in which there is abnormal proliferation ofcells of the lymphatic system), chronic rheumatoid arthritis,arteriosclerosis, restenosis, and diabetic retinopathy. Proliferativediseases that are hereby incorporated by reference include thosedescribed in U.S. Pat. Nos. 5,639,600 and 7,087,648.

Inflammatory Disorders and Diseases

It has recently been reported that PHGDH gene expression, dictated byIL-2R signaling, is a crucial event for DNA synthesis during S phase ofactivated T cells. Jun do Y et al., Cell Immunol. 2014 February;287(2):78-85. Compounds according to the invention are useful in thetreatment of inflammatory or obstructive airways diseases, resulting,for example, in reduction of tissue damage, airways inflammation,bronchial hyperreactivity, remodeling or disease progression.Inflammatory or obstructive airways diseases to which the presentinvention is applicable include asthma of whatever type or genesisincluding both intrinsic (non-allergic) asthma and extrinsic (allergic)asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample antiinflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”. “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterized by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is an disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitits, atompic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, and other inflammatory or allergic conditions of theskin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from Systemiclupus erythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Metabolic Disease

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome or obesity.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsulated matrices of the compound inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting PHGDH activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting PHGDH, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound. In certainembodiments, the invention relates to a method of irreversiblyinhibiting PHGDH, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Another embodiment of the present invention relates to a method ofinhibiting PHGDH in a patient comprising the step of administering tosaid patient a compound of the present invention, or a compositioncomprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting PHGDH, or a mutant thereof, activity in a patient comprisingthe step of administering to said patient a compound of the presentinvention, or a composition comprising said compound. According tocertain embodiments, the invention relates to a method of irreversiblyinhibiting PHGDH, or a mutant thereof, activity in a patient comprisingthe step of administering to said patient a compound of the presentinvention, or a composition comprising said compound. In otherembodiments, the present invention provides a method for treating adisorder mediated by PHGDH, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal©); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™.Letrozole is marketed under the trade names Femara™ or Femar™Aminoglutethimide is marketed under the trade name Orimeten™. Acombination of the invention comprising a chemotherapeutic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecin and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtubulin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;colchicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™ Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the Axl receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-O-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; othergeldanamycin related compounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan*), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group (“PG”),leaving group (“LG”), or transformation condition is depicted, one ofordinary skill in the art will appreciate that other protecting groups,leaving groups, and transformation conditions are also suitable and arecontemplated. Such groups and transformations are described in detail inMarch's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 5^(th) Edition, John Wiley & Sons,2001, Comprehensive Organic Transformations, R. C. Larock, 2^(nd)Edition, John Wiley & Sons, 1999, and Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, the entirety of each of which is hereby incorporated hereinby reference.

As used herein, the phrase “leaving group” (LG) includes, but is notlimited to, halogens (e.g. fluoride, chloride, bromide, iodide),sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate,nosylate, triflate), diazonium, and the like.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Examples ofsuitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Suitable aminoprotecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In certain embodiments, compounds of the present invention of formula I,or subformulae thereof, are generally prepared according to Scheme I setforth below:

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. “March's Advanced OrganicChemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley &Sons, New York: 2001, the entirety of which is incorporated herein byreference. Such interconversions may require one or more of theaforementioned techniques, and certain methods for synthesizingcompounds of the invention are described below.

In one aspect, certain compounds of the present invention of formula I,or subformulae thereof, are generally prepared according to Scheme 1 setforth below:

In Scheme 1 above, R′ is a group such as C₁₋₆ aliphatic, 5- to8-membered aromatic ring, or other functionality compatible with anester; and R¹, R², R³, and R⁶ are selected consistent with formula Iabove and below and in classes and subclasses as described herein.

In one aspect, the present invention provides methods for preparingcompounds of formula GS4 as described in Scheme 1. An optionallysubstituted benzaldehyde may be condensed with an azidoacetate in thepresence of base such as sodium hydroxide or sodium methoxide to giveintermediate GS1. Heating GS1 in a solvent such as toluene (e.g., atreflux) provides the indole-2-carboxylate ester. In some embodiments,the indole nitrogen is alkylated using an appropriate alkyl halide suchas methyl or ethyl iodide and a suitable base such as, but not limited,to sodium hydride, potassium tert-butoxide, or potassium carbonate in asuitable solvent to provide GS3. In some embodiments, the ester of GS3is hydrolyzed using a base such as LiOH, KOH, or NaOH in a solvent suchas a mixture of water and THE to provide an intermediate used in thesynthesis of compounds of the invention of general structure GS4.

Alternatively, in some embodiments GS3 may be treated with appropriatereagents such as POCl₃ and DMF to give GS3′. In some embodiments, thealdehyde in GS3′ is then reduced to a methyl group with appropriatereagents such as Et₃SiH and TFA to give GS4′. Finally, in someembodiments, hydrolysis of the ester in GS4′ provides an intermediateused in the synthesis of compounds of the invention of general structureGS5′.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 2 setforth below:

Scheme 2 describes an alternate route to prepare compounds of formulaGS3. In some embodiments, treatment of an aniline with a nitritecompound and a ketoacetate of choice in a suitable solvent (for example,a mixture of ethanol/water) produces an aryl hydrazine intermediate thatreacts with the ketoacetate (such as ethyl 2-methyl-3-oxo-butanoate) toprovide GS5. Treatment of GS5 with TFA with heat, e.g., reflux, providesgeneral intermediate GS3 that can be elaborated to GS4 and GS7 asdescribed above.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 3 setforth below:

Intermediate GS6 in Scheme 3 can be accessed as described for GS3, whereR³ is an methoxy group. Hydrolysis of the methoxy group and ester withboron tribromide in dichloromethane followed by treatment with thionylchloride in methanol provides intermediate ester GS7. GS7 can behydrolyzed to the acid as described above for GS4 to yield GS8.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 4 setforth below:

Intermediate GS9 in Scheme 4 can be accessed as described for GS3, whereR² and R³ are methoxy groups. Hydrolysis of the methoxy groups and esterwith boron tribromide in dichloromethane followed by treatment with1,2-dibromoethane and a base such as cesium carbonate in as suitablesolvent such as DMF provides intermediate ester GS10. GS10 can behydrolyzed to the acid as described above for GS4 to yield GS11.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 5 setforth below:

Intermediates such as GS12, Scheme 5 can be accessed by exposing alcoholintermediate GS7 to triflic anhydride and pyridine in dichloromethane.Cross coupling with the corresponding boronic acid under standard Suzukicoupling conditions with a catalyst such as Pd(PPh₃)₄ and a base such ascesium carbonate in an appropriate solvent such as dioxane/water cangive rise to GS3 that can be elaborated to GS4 as described previously.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 6 setforth below:

N-(oxomethylene)sulfamoyl chloride when treated with reagents such astert-butanol in dichloromethane can provide compounds such as GS13 inScheme 6. N-(oxomethylene)sulfamoyl chloride can be alternativelyconverted to GS14 with acetic acid in dichloromethane.N-(oxomethylene)sulfamoyl chloride can further be derivatized to GS28 byreaction under conditions such as 2-bromoethanol, pyrimidin-2-amine, andtriethylamine in dichloromethane.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 7 setforth below:

A bromophenyl acetonitrile compound can be reacted with tert-butylN,N-bis(2-chloroethyl)carbamate and sodium hydride inN,N-dimethylformamide to form compounds such as GS15, Scheme 7.Hydrolysis of the nitrile to the amide GS16 can be achieved via exposureto hydrogen peroxide and potassium carbonate in dimethyl sulfoxide orequivalent conditions. Formation of amine GS17 can be accomplished byreacting the amide with PhI(CF₃CO₂)₂ in acetonitrile/water. The bromidecan be removed under hydrogenation conditions using palladium on carbonin methanol to form GS18. Alternatively, amide GS19 can be installedunder coupling conditions with acetamide, Pd₂(dba)₃, Xantphos, andcesium carbonate in N,N-dimethylformamide with heating. The bromide canalso be converted to ester GS20 with Pd(dppf)Cl₂·CH₂Cl₂ andtriethylamine in ethanol in the presence of carbon monoxide (50 psi).

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 8 setforth below:

Bromide GS15 in Scheme 8 can be converted to ester GS21 with anappropriate catalyst such as Pd(dppf)Cl₂·CH₂Cl₂ and triethylamine inethanol under carbon monoxide (50 psi). GS21 and GS22 can be formed asdescribed above for GS16 and GS17.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 9 setforth below:

A benzylpiperidinone or benzylpyrrolidinone can be treated with anoptionally substituted aryl bromide or iodide with n-butyllithium in THEto form an alcohol such as GS24 (Scheme 9). Alternatively,benzylpiperidinone or benzylpyrrolidinone can react with anunsubstituted or bromo-substituted aryl Grignard reagent in THE to alsoform compounds such as GS24. Amide GS25 can be formed by treatment withsulfuric acid in acetonitrile. The amide can then be hydrolyzed to theamine GS26 with hydrochloric acid. The bromide derivatives of GS26 canbe converted to the ester GS27 with reagents such as Pd(dppf)Cl₂·CH₂Cl₂and triethylamine in ethanol under carbon monoxide (50 psi).

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 10 setforth below:

To prepare compounds such as GS33, a solution of paraformaldehyde indichloromethane is bubbled with HCl (gas). Then, the correspondingchloro alcohol is added to form compounds such as GS29 (Scheme 10). Thisintermediate can then be treated with bromophenyl acetonitrile andsodium hydride in N,N-dimethylformamide to yield compounds like GS30.Exposure of GS30 to potassium carbonate and hydrogen peroxide indimethyl sulfoxide can give amide compounds like GS31. Reduction of theamide is achieved with PhI(CF₃CO₂)₂, or a similar reagent likePhI(OAc)₂, in acetonitrile and water to form GS32. The bromide can beconverted to ester GS33 by coupling with Pd(dppf)Cl₂·CH₂Cl₂ andtriethylamine in ethanol in the presence of carbon monoxide (50 psi)with heating.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 11 setforth below:

A bromo- and methyl-disubstituted pyridine or pyridazine in anappropriate solvent such as acetonitrile or carbon tetrachloride can betreated with a radical initiator such as 2,2-azobisisobutyronitrile(AIBN) and N-bromosuccinimide (NBS) and heated to form compounds such asGS34 (Scheme 11). This can then be added to a solution of trimethylsilylcyanide (TMSCN) and tetrabutylammonium fluoride (TBAF) in acetonitrileto yield compound like GS35. GS35 can be converted to GS36 as describedabove for GS30. GS37 can be formed as described above for GS33. GS38 andGS39 can be formed as described above for GS31 and GS32, respectively.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 12 setforth below:

An optionally substituted benzoic acid can be treated with thionylchloride in methanol and heated to form GS40 (Scheme 12). GS41 and GS42can be synthesized as described above for GS34 and GS35, respectively.GS42 can be further elaborated to GS43, GS44 and GS45 as described abovefor GS30, GS31, and GS32.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 13 setforth below:

When X═Br for GS45 the intermediate can be converted to the nitrile GS46by coupling with copper cyanide and copper iodide in1-methyl-2-pyrrolidinone with heating.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 14 setforth below:

Intermediate GS30 can be coupled with(3-ethoxy-3-oxo-propanoyl)oxypotassium with allyl(chloro)palladium,dimethylaminopyridine, and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP) in xylene with heat to form allyl ester GS47 (Scheme 14). Thisester portion can be further alkylated with the corresponding alkylhalide under basic conditions, using either LiHMDS or sodium hydride, ina solvent such as N,N-dimethylformamide or tetrahydrofuran, to give GS48as a mono or bis-alkylated product. GS48 can be further elaborated toGS49 and GS50 as described above for GS31 and GS32, respectively.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 15 setforth below:

A 4-6 membered ring oxo-ketone can be reacted with(±)-2-methylpropane-2-sulfinamide and Ti(OEt)₄ in tetrahydrofuran toform intermediates such as GS51 (Scheme 15). The corresponding of1-bromo-4-iodo-benzene (optionally substituted with various R such as H,F, Cl, Me, OMe) in tetrahydrofuran can be treated with n-butyllithiumwith cooling. Then a solution of GS51 in tetrahydrofuran can be added tothe solution to give GS52. The bromide can be converted to ester GS53via coupling with Pd(dppf)Cl₂·CH₂Cl₂ and TEA in a mixture of methanoland dimethyl sulfoxide under carbon monoxide (50 psi) with heating.Deprotection of the amine can be accomplished by treating GS53 withiodine in a mixture of tetrahydrofuran and water or with a solution ofhydrochloric acid in dioxane with ethanol as the solvent to give GS54.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 16 setforth below:

Intermediates such as GS52 (Scheme 16) can be coupled with anorganometallic reagent such as bromo-(2-ethoxy-2-oxo-ethyl)zinc, acatalyst such as Pd₂(dba), and a ligand such as XPhos in an appropriatesolvent such as tetrahydrofuran, usually with heating, to form GS55.GS55 can be deprotected to form amine GS56 as previously described forGS54.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 17 setforth below:

Compounds such as GS52 (Scheme 17) can be protected by reacting withSEMCI in tetrahydrofuran with a base such as sodium hydride. Theprotected GS57 can then be coupled as described for GS55 above. GS58 canthen be alkylated with methyl iodide using LDA, NaH or LiHMDS as thebase in tetrahydrofuran to form either the mono or bis-alkylatedproducts if excess reagents are used. GS59 is deprotected to form amineGS60 using the method previously described for GS56.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 18 setforth below:

The ester of compounds such as GS57 (Scheme 18) can be saponified toacid GS61 by exposure to a base such as lithium hydroxide in a solventsuch as a mixture of water and tetrahydrofuran. Acid GS61 can then bealkylated with 3-bromoprop-1-ene by addition of potassium carbonate inDMF to form GS62. GS62 can be further alkylated with a variety of groupsusing either the alkyl bromide or alkyl iodide with LiHMDS, LDA, or NaHas the base in an appropriate solvent such as DMF or tetrahydrofuran toform the mono or bis-alkylated product GS63. The amine GS64 is obtainedby deprotection with hydrochloric acid/dioxane in ethanol.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 19 setforth below:

The amine of intermediate GS33 can be protected with a variety ofprotecting groups including Boc and SEM groups. This protectedintermediate GS65 ester (Scheme 19) can then be reduced to the alcoholusing lithium aluminum hydride or lithium borohydride in a solvent suchas THE to yield GS66. The alcohol can then be transformed to themesylate using methanesulfonyl chloride (MsCl), a base such as TEA, andDMAP in an appropriate solvent such as DCM. The mesylate GS67 can beconverted to the nitrile GS68 by reacting it with sodium cyanide andsodium iodide in DMF. Finally, deprotection of the groups on the aminecan be achieved with HCl/dioxane in ethanol or trifluoroacetic acid indichloromethane to yield amine GS69.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 20 setforth below:

Intermediates such as GS52 in Scheme 20 can be deprotected withhydrochloride/dioxane in ethanol to form GS70. A Cbz protecting groupcan be then installed by treated GS70 with benzyl carbonochloridate anda base such as sodium carbonate in a solvent such as a mixture ofTHF/water. Coupling of GS71 and triisopropyl(sulfanyl)silane with acatalyst such as palladium acetate, ligand such as triphenylphosphine,and base such as cesium carbonate in an appropriate solvent such astoluene can give rise to intermediates such as GS72. Treatment of GS72with N-chlorosuccinimide (NCS) in acetic acid and water can form thesulfonyl chloride GS73 which can be converted to the sulfonyl amine GS74when exposed to ammonia in tetrahydrofuran. Coupling of the amine withan acid can be achieved with conditions such as EDCI, DMAP and aceticacid in DMF to form amide GS75. Finally, the Cbz protecting group can beremoved under hydrogenation conditions with Pd/C in methanol or ethanolunder hydrogen gas (50 psi).

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 21 setforth below:

In Scheme 21 above, variables R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ areselected consistent with formula I, and subformulae thereof, describedabove and below. Conversion of the acid group in GS4 (Scheme 21) to theacid chloride can be achieved using procedures well known to one ofskills in the art. For example, the acid GS4 can be treated with oxalylchloride or thionyl chloride with a catalytic amount of DMF in a solventsuch as DCM. Reaction of acyl chloride intermediate with an amine ofchoice with a base such as TEA or DIPEA can afford compounds such asGS77. Hydrolysis of the ester can be achieved with lithium hydroxide intetrahydrofuran and water to form the final acid product GS78.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 22 setforth below:

In Scheme 22 above, variables R¹, R², and R³ are selected consistentwith formula I, and subformulae thereof, described above and below. Whenintermediate GS77 (Scheme 22) is an hydroxyindole, it can be furtheralkylated using the corresponding alkyl-chloride, bromide or iodideunder basic condition using conditions such as potassium carbonate inDMF to give GS79. The ester can then be hydrolyzed in similar fashion asdescribed for GS78 to give final product GS80.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 23 setforth below:

In Scheme 23 above, variables R¹, R², R³, R⁴, and R⁵ are selectedconsistent with formula I, and subformulae thereof, described above andbelow. Coupling of amine compounds such as GS64 (Scheme 23) with acidGS4 is accomplished as described for GS77. Deprotection of the allylgroup with Pd(PPh₃)₄ and morpholine in tetrahydrofuran provides the acidproduct GS82.

In another aspect, compounds of the present invention of formula I, orsubformulae thereof, are generally prepared according to Scheme 24 setforth below:

In Scheme 24 above, variables R¹, R², R³, R⁴, and R⁵ are selectedconsistent with formula I, and subformulae thereof, described above andbelow. A variety of tertiary amines (Scheme 24), where the 4-6 memberedcyclic amine protected (with Bn, Boc, etc.), can be coupled with acidGS4 to form GS83 in a similar fashion as described for GS77. The cyclicamine can then be deprotected under standard conditions, such ashydrogenation with Pd/C for benzyl protection or hydrochloric acid inethyl acetate or methanol for Boc deprotection to give GS84. Coupling ofthis cyclic amine N-acetylsulfamoyl chloride and triethylamine indichloromethane provides final product GS85. If R⁴ is an ester, it canfurther be reduced to the acid under standard conditions as describedfor GS78 to give final product GS86.

Alternatively, cyclic amine GS84 can be coupled with tert-butylN-chlorosulfonylcarbamate with triethylamine in dichloromethane to formGS87. The Boc group can be removed under standard deprotectionconditions such as hydrochloric acid in methanol to give GS88. Thesulfamoyl group can then be coupled with various acyl or amide chlorideswith triethylamine in dichloromethane to form the final product GS89.

Abbreviations

-   -   Ac: acetyl    -   AcOH: acetic acid    -   ACN: acetonitrile    -   Ad: adamantly    -   AIBN: 2,2′-azo bisisobutyronitrile    -   Anhyd: anhydrous    -   Aq: aqueous    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BH₃: Borane    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   Boc₂O: di-tert-butyl dicarbonate    -   BPO: benzoyl peroxide    -   ^(n)BuOH: n-butanol    -   cSFC: chiral supercritical fluid chromatography    -   COD: cyclooctadiene    -   d: days    -   DAST: diethylaminosulfur trifluoride    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DIBAL-H: diisobutylaluminum hydride    -   DIPEA or DIEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DME: 1,2-dimethoxyethane    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMSO-dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   ee: enantiomeric excess    -   ESI: electrospray ionization    -   EA: ethyl acetate    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   FA: formic acid    -   h: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    -   hexafluorophosphate    -   HCl: hydrochloric acid    -   HPLC: high performance liquid chromatography    -   HOAc: acetic acid    -   IPA: isopropyl alcohol    -   KHMDS: potassium hexamethyldisilazide    -   K₂CO₃: potassium carbonate    -   LAH: lithium aluminum hydride    -   LDA: lithium diisopropylamide    -   m-CPBA: meta-chloroperbenzoic acid    -   M: molar    -   MeCN: acetonitrile    -   MeOH: methanol    -   Me₂S: dimethyl sulfide    -   MeONa: sodium methylate    -   MeI: iodomethane    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MOMCl: methyl chloromethyl ether    -   MsCl: methanesulfonyl chloride    -   MTBE: methyl tert-butyl ether    -   NaNO₂: sodium nitrite    -   Na₂SO₄: sodium sulfate    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NaOH: sodium hydroxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   Pd/C: Palladium on Carbon    -   Pd(OAc)₂: Palladium Acetate    -   PBS: phosphate buffered saline    -   PE: petroleum ether    -   POCl₃: phosphorus oxychloride    -   PPh₃: triphenylphosphine    -   Rel: relative    -   R.T. or rt: room temperature    -   sat: saturated    -   SEMCl: chloromethyl-2-trimethylsilylethyl ether    -   SFC: supercritical fluid chromatography    -   SOCl₂: sulfur dichloride    -   tBuOK: potassium tert-butoxide    -   TBAB: tetrabutylammonium bromide    -   TEA: triethylamine    -   Tf: trifluoromethanesulfonate    -   TfAA: trifluoromethanesulfonic anhydride    -   TFA: trifluoracetic acid    -   TIPS: triisopropylsilyl    -   THF: tetrahydrofuran    -   THP: tetrahydropyran    -   TLC: thin layer chromatography    -   TMEDA: tetramethylethylenediamine    -   pTSA: para-toluenesulfonic acid    -   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Unless otherwisestated, one or more tautomeric forms of compounds of the examplesdescribed hereinafter may be prepared in situ and/or isolated. Alltautomeric forms of compounds of the examples described hereafter shouldbe considered to be disclosed. Temperatures are given in degreescentigrade. If not mentioned otherwise, all evaporations are performedunder reduced pressure, preferably between about 15 mm Hg and 100 mm Hg(=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.,microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated. Optical rotations were measured in MeOH.

Proton NMR (¹H NMR) is conducted in deuterated solvent. In certaincompounds disclosed herein, one or more 1H shifts overlap with residualprotio solvent signals; these signals have not been reported in theexperimental provided hereinafter

Analytical instruments Table: LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical cSFC AgilentTechnologies 1290 Infinity Prep-cSFC Waters SFC Prep 80

For acidic LCMS data:

LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS2020equipped with electro-spray ionization and quadruple MS detector [ES+veto give MH⁺] and equipped with Chromolith Flash RP-18e 25*2.0 mm,eluting with 0.0375 vol % TFA in water (solvent A) and 0.01875 vol % TFAin acetonitrile (solvent B).

For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18,2.1×50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1×30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃·H₂O in water (solvent A) and acetonitrile (solvent B).

Intermediates 4,5-Dichloro-1-methyl-indole-2-carboxylic acid(Intermediate A)

Step 1—Methyl (Z)-2-azido-3-(2, 3-dichlorophenyl)prop-2-enoate

To a solution of sodium methoxide (11.1 g, 205 mmol) in anhydrousmethanol (80 mL) was added a mixed solution of 2,3-dichlorobenzaldehyde(12.0 g, 68.5 mmol) and ethyl 2-azidoacetate (26.5 g, 205 mmol) inanhydrous methanol (80 mL) at −50° C. After stirring at −50° C. for 2hrs, the mixture was warmed to rt, and stirred for 14 hrs. Oncompletion, the suspension was poured onto ice and the azido derivativewas collected by filtration, washed with cold water. The filter cake wasdried in vacuo and purified by column chromatography (petroleumether/ethyl acetate=10/1) to give the title compound as a white solid.¹H NMR (400 MHz, CDCl3) δ=8.06 (dd, J=1.3, 8.0 Hz, 1H), 7.45 (dd, J=1.4,8.0 Hz, 1H), 7.30-7.24 (m, 2H), 3.97 (s, 3H).

Step 2—Methyl 4, 5-dichloro-1H-indole-2-carboxylate

A solution of methyl (Z)-2-azido-3-(2, 3-dichlorophenyl)prop-2-enoate(7.80 g, 28.6) in toluene (150 mL) was stirred at 120° C. for 16 hrs. Oncompletion, the toluene was removed in vacuo to give a residue. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=12/1 to 5/1) to give the title compound as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=12.52 (br. s., 1H), 7.47-7.41 (m, 2H), 7.12 (d,J=2.1 Hz, 1H), 3.90 (s, 3H).

Step 3—Methyl 4,5-dichloro-1-methyl-indole-2-carboxylate

To a solution of methyl 4,5-dichloro-1H-indole-2-carboxylate (4.50 g,18.4 mmol) in N,N-dimethylformamide (40 mL) was added potassiumcarbonate (6.37 g, 46.1 mmol) and iodomethane (10.4 g, 73.7 mmol). Themixture was stirred at 60° C. for 16 hrs. On completion, the reactionmixture was concentrated in vacuo to remove solvent. The residue wasdiluted with water 30 mL and extracted with dichloromethane (3×15 mL).The combined organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (petroleum ether/ethyl acetate=8/1 to 3/1) to givethe title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.69(d, J=8.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.22 (s, 1H), 4.05 (s, 3H),3.89 (s, 3H).

Step 4-4, 5-Dichloro-1-methyl-indole-2-carboxylic acid

To a solution of methyl 4,5-dichloro-1-methyl-indole-2-carboxylate (4.10g, 15.8 mmol) in a mixture solvent of tetrahydrofuran (40 mL) and water(10 mL) was added lithium hydroxide (1.14 g, 47.6 mmol). The mixture wasstirred at rt for 16 hrs. On completion, the reaction mixture wasconcentrated in vacuo. The residue was acidified with 1M hydrochloricacid until pH=3. During which, a fine precipitate was formed and it wasfiltered and the filter cake was washed with water, dried under vacuumto give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=13.35 (br. s.,1H), 7.61 (d, J=8.9 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.14 (s, 1H), 4.03(s, 3H).

4-Chloro-5-methoxy-1-methyl-indole-2-carboxylic acid (Intermediate B)

Step 1—Methyl-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate

To a solution of sodium methoxide (2.38 g, 43.9 mmol) in methanol (40mL) was added 2-chloro-3-methoxy-benzaldehyde (2.50 g, 14.6 mmol) andethyl 2-azidoacetate (4.73 g, 36.7 mmol) at −50° C. under nitrogenatmosphere. The mixture was stirred at the same temperature for 2 hrs,then warmed to rt and stirred for 14 hrs. On completion, the suspensionwas poured into ice and the azido derivative was collected by filtrationand washed with cold water. The filter cake was dried over in vacuo togive the crude product. The crude product was purified by silica gelchromatography (petroleum ether:ethyl acetate=6:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=7.77 (dd, J=1.0, 8.0 Hz, 1H), 7.35(s, 1H), 7.31-7.26 (m, 1H), 6.95 (dd, J 1.3, 8.0 Hz, 1H), 3.96 (s, 3H),3.94 (s, 3H).

Step 2—Methyl-4-chloro-5-methoxy-1H-indole-2-carboxylate

Methyl-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate (2.00 g, 7.47mmol) was dissolved in xylol (200 mL) and the mixture was stirred at180° C. for 30 min. On completion, the reaction mixture was concentratedin vacuo to afford a residue. The residue was triturated with (petroleumether:ethyl acetate=10:1) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=12.16 (br. s., 1H), 7.40 (d, J=9.0 Hz, 1H), 7.24 (d, J=9.0Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).

Step 3—methyl 4-chloro-5-methoxy-1-methyl-indole-2-carboxylate

To a solution of methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (920mg, 3.84 mmol) in N, N-dimethylformamide (15 mL) was added potassiumcarbonate (1.33 g, 9.60 mmol) and iodomethane (2.18 g, 15.4 mmol). Theresulting mixture was warmed to 60° C. and stirred for 3 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to afford aresidue. The residue was diluted with water (30 mL) and extracted withdichloromethane (3×25 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.57 (d, J=9.0 Hz, 1H), 7.30(d, J=9.0 Hz, 1H), 7.10 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.86 (s,3H).

Step 4—4-Chloro-5-methoxy-1-methyl-indole-2-carboxylic acid

To a solution of methyl 4-chloro-5-methoxy-1-methyl-indole-2-carboxylate(950 mg, 3.74 mmol) in tetrahydrofuran (16 mL) and water (4 mL) wasadded lithium hydroxide (268 mg, 11.2 mmol). The resulting mixture wasstirred at rt for 3 hrs. On completion, the reaction mixture wasconcentrated in vacuo and the residue was acidified with 2N hydrochloricacid until pH=3. During which, a fine precipitate was formed. Theprecipitate was filtered and the filter cake was washed with water,dried in vacuo to give the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ=13.19 (br. s., 1H), 7.56 (d, J=9.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H),7.08 (s, 1H), 4.02 (s, 3H), 3.88 (s, 3H).

4-Chloro-1-methyl-indole-2-carboxylic acid (Intermediate C)

Step 1—Methyl (Z)-2-azido-3-(2-chlorophenyl)prop-2-enoate

To a solution of sodium methoxide (11.5 g, 213 mmol) in methanol (100mL) was added a solution of 2-chlorobenzaldehyde (10.0 g, 71.1 mmol) andethyl azidoacetate (27.5 g, 213 mmol) in methanol (50.0 mL) dropwise at−40° C. under nitrogen. After the reaction mixture was stirred at −40°C. for 1 hr, the reaction mixture was stirred at rt for 16 hrs. Oncompletion, the resulting suspension was poured onto ice, filtrated andthe filter cake was washed with cold water. The yellow solid was driedin vacuo and purified by silica gel chromatography (petroleumether:ethyl acetate=20:1) to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=8.20 (dd, J=1.8, 7.7 Hz, 1H), 7.44 (dd, J=1.6, 7.8 Hz, 1H),7.37-7.23 (m, 3H), 3.96 (s, 3H).

Step 2—Methyl 4-chloro-1H-indole-2-carboxylate

A solution of methyl (Z)-2-azido-3-(2-chlorophenyl)prop-2-enoate (12.9g, 54.2 mmol) in toluene (400 mL) was stirred at 120° C. for 20 hrsunder nitrogen. On completion, the reaction mixture was concentrated invacuo to give a crude product, which was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=9.08 (br. s., 1H), 7.38-7.33 (m,2H), 7.25 (t, J=12 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 3.99 (s, 3H).

Step 3—Methyl 4-chloro-1-methyl-1H-indole-2-carboxylate

To a solution of methyl 4-chloro-1H-indole-2-carboxylate (5.30 g, 25.2mmol) and potassium carbonate (10.4 g, 75.8 mmol) inN,N-dimethylformamide (70.0 mL) was added methyl iodide (10.7 g, 75.8mmol) and the reaction mixture was stirred at 60° C. for 4 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to give acrude product, which was purified by silica gel chromatography(petroleum ether:ethyl acetate=5:1) to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ=7.63 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H),7.28-7.17 (m, 2H), 4.06 (s, 3H), 3.88 (s, 3H).

Step 4—4-Chloro-1-methyl-indole-2-carboxylic acid

To a solution of methyl 4-chloro-1-methyl-indole-2-carboxylate (5.60 g,25.0 mmol) in a mixture of tetrahydrofuran (40.0 mL) and water (40.0 mL)was added lithium hydrate (2.40 g, 100 mmol) and the reaction mixturewas stirred at rt for 16 hrs. On completion, the reaction mixture wasconcentrated in vacuo and the aqueous phase was acidified with aqueoushydrochloric acid (4M) until pH=3. Then the aqueous phase was extractedwith ethyl acetate (3×200 mL). The combined layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo to givethe title compound. ¹H NMR (400 MHz, DMSO-d6) δ=13.21 (br. s., 1H), 7.60(d, J=8.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.18(s, 1H), 4.01 (s, 3H).

4-Chloro-5-fluoro-1-methyl-indole-2-carboxylic acid (Intermediate D)

Step 1—Ethyl (2E)-2-[(3-chloro-4-fluoro-phenyl) hydrazono] propanoate

To a solution of 3-chloro-4-fluoro-aniline (15.0 g, 103 mmol) in ethanol(15 mL) and water (15 mL) was added hydrochloric acid (37%, 30 mL). Themixture was cooled to −5° C., and then a solution of NaNO₂ (8.00 g, 116mmol) in water (40 mL) was added dropwise while the temperature wasmaintained below 5° C. A cold solution of ethyl 2-methyl-3-oxo-butanoate(15.0 g, 104 mmol) and sodium acetate (30.0 g, 366 mmol) in a mixturesolvent of ethanol (75 mL) and water (30 mL) was added to the reactionmixture, and the reaction mixture was stirred at −5° C. for 4 hours. Oncompletion, the reaction mixture was extracted with dichloromethane andconcentrated in vacuo. The residue was purified by column chromatography(petroleum ether/ethyl acetate=30:1 to 10:1) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ=7.33-7.25 (m, 1H), 7.05 (t, J=8.8 Hz, 1H),6.98-6.90 (m, 1H), 4.29 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.38 (t, J=7.2Hz, 3H).

Step 2—Ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and Ethyl6-chloro-5-fluoro-1H-indole-2-carboxylate

A solution of ethyl (2E)-2-[(3-chloro-4-fluoro-phenyl) hydrazono]propanoate (6.70 g, 25.9 mmol) in trifluoroacetic acid (30 mL) wasrefluxed at 80° C. for 12 hours. On completion, the solvent wasevaporated in vacuo, and the residue was diluted in ethyl acetate andwas washed with a saturated aqueous sodium hydrogen carbonate solutionand brine, then dried over sodium sulfate and concentrated. The residuewas purified by silica gel column chromatography (petroleum ether/ethylacetate=30:1 to 20:1) to give ethyl4-chloro-5-fluoro-1H-indole-2-carboxylate (150 mg, 3% yield), ethyl6-chloro-5-fluoro-1H-indole-2-carboxylate (700 mg, 11% yield) and amixture of ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and ethyl6-chloro-5-fluoro-1H-indole-2-carboxylate (3.0 g) as yellowish solid.Ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate ¹H NMR (300 MHz,DMSO-d6) δ=12.11 (br. s., 1H), 7.67 (d, J=10.0 Hz, 1H), 7.57 (d, J=6.4Hz, 1H), 7.15 (d, J=1.1 Hz, 1H), 4.35 (q, J=9.2 Hz, 2H), 1.33 (t, J=9.2Hz, 3H). Mixture ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate & ethyl6-chloro-5-fluoro-1H-indole-2-carboxylate ¹H NMR (300 MHz, DMSO-d6)δ=12.38 (br. s., 0.5H), 12.11 (br. s., 0.5H), 7.66 (d, J=10.0 Hz, 0.5H),7.57 (d, J=6.4 Hz, 0.5H), 7.45 (dd, J=4.0, 8.9 Hz, 0.5H), 7.37-7.26 (m,0.5H), 7.14 (dd, J=1.5, 5.8 Hz, 0.5H), 4.56-4.06 (m, 2H), 1.61-1.04 (m,3H).

Step 3—Ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate and ethyl6-chloro-5-fluoro-1-methyl-indole-2-carboxylate

To a solution of a mixture of ethyl4-chloro-5-fluoro-1H-indole-2-carboxylate and ethyl6-chloro-5-fluoro-1H-indole-2-carboxylate (5.00 g, 20.7 mmol) inN,N-dimethylformamide (20 mL) was added potassium carbonate (11.4 g,82.7 mmol) and iodomethane (14.7 g, 103 mmol). Then the mixture wasstirred at 60° C. for 12 hrs. On completion, the residue was dilutedwith water (100 mL), extracted with ethyl acetate (3×80 mL). The organiclayers were dried over anhydrous sodium sulfate, filtrated andconcentrated. The residue was purified by prep-SFC (Condition:Base-MeOH; Column: AD (250 mm*30 mm, 10 um) to give ethyl4-chloro-5-fluoro-1-methyl-indole-2-carboxylate (2.6 g, 49% yield) andethyl 6-chloro-5-fluoro-1-methyl-indole-2-carboxylate (2.4 g, 45% yield)as yellow solids. Ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate¹H NMR (400 MHz, CDCl3) δ=7.38 (s, 1H), 7.31-7.22 (m, 1H), 7.22-7.15 (m,1H), 4.42 (q, J=7.3 Hz, 2H), 4.09 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). Ethyl6-chloro-5-fluoro-1-methyl-indole-2-carboxylate ¹H NMR (400 MHz, CDCl3)δ=7.49-7.37 (m, 2H), 7.24 (s, 1H), 4.40 (q, J=7.3 Hz, 2H), 4.09 (s, 3H),1.45 (d, J=7.2 Hz, 3H).

Step 4—4-Chloro-5-fluoro-1-methyl-indole-2-carboxylic acid

To a mixture of ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate(2.60 g, 10.2 mmol) in tetrahydrofuran (20 mL) and water (20 mL) wasadded lithium hydroxide (1.71 g, 40.7 mmol). Then the mixture wasstirred at rt for 12 hrs. On completion, the mixture was concentrated invacuum. The residue was diluted water (50 mL). The mixture was acidifiedwith 2N hydrochloric acid until pH=3 and extracted with ethyl acetate(3×50 mL). The organic layers were dried over anhydrous sodium sulfate,filtrated and concentrated to give the title compound. ¹H NMR (400 MHz,DMSO-d6) δ=7.75-7.57 (m, 1H), 7.39 (t, J=9.4 Hz, 1H), 7.19 (s, 1H), 4.05(s, 3H).

Step 4—6-Chloro-5-fluoro-1-methyl-indole-2-carboxylic acid

To a solution of ethyl 6-chloro-5-fluoro-1-methyl-indole-2-carboxylate(2.40 g, 9.39 mmol) in a mixture solvent of tetrahydrofuran (20 mL) andwater (20 mL) was added lithium hydroxide (1.58 g, 37.6 mmol). Themixture was stirred at rt for 12 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was diluted water (50 mL), acidifiedwith 2N hydrochloric acid until pH=3 and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulfate,filtrated and concentrated to give the title compound (2.10 g, 98%yield) as yellowish solid. ¹H NMR (400 MHz, DMSO-d6) δ=13.18 (br. s.,1H), 8.07-7.85 (m, 1H), 7.68 (d, J=9.8 Hz, 1H), 7.21 (s, 1H), 4.09 (s,3H).

4-Chloro-1,5-dimethyl-1H-indole-2-carboxylic acid (Intermediate E)

Step 1—(2-Chloro-3-methylphenyl)methanol

To a solution of 2-chloro-3-methyl-benzoic acid (30 g, 175 mmol) inanhydrous tetrahydrofuran (240 mL) was added dropwise BH₃·Me₂S (10 M, 21mL) under nitrogen. The reaction mixture was stirred at reflux at 70° C.for 12 hrs. On completion, the reaction mixture was quenched withmethanol (50 mL), diluted with water (230 mL) and extracted with ethylacetate (2×300 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the crude product. The crude product was purified bysilica gel chromatography (petroleum ether:ethyl acetate=5:1) to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.42-7.34 (m, 1H), 7.24(d, J=4.8 Hz, 2H), 5.36 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 2.32(s, 3H).

Step 2—2-Chloro-3-methylbenzaldehyde

To a solution of (2-chloro-3-methyl-phenyl)methanol (26.2 g, 167 mmol)in dichloromethane (350 mL) was added manganese dioxide (116 g, 1.34mol) under nitrogen. After, the reaction mixture was stirred at rt for12 hrs. The solid was filtered, and the filtrate was concentrated undervacuum. The residue was purified by column chromatography (eluted withpetroleum ether:ethyl acetate=20:1) to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ=10.42-10.34 (m, 1H), 7.68 (t, J=8.2 Hz, 2H), 7.42(t, J=7.5 Hz, 1H), 2.39 (s, 3H).

Step 3—(Z)-Methyl 2-azido-3-(2-chloro-3-methylphenyl)acrylate

To a solution of MeONa (17.2 g, 319 mmol) in methanol (150 mL) was addeda solution of ethyl 2-azidoacetate (41.2 g, 319 mmol) and2-chloro-3-methyl-benzaldehyde (16.4 g, 106 mmol) in methanol (150 mL)dropwise at −20° C. After the mixture was stirred at −20° C. for 2 hrs,it was warmed up to rt for 12 hrs. During this time a fine precipitatewas formed. The suspension was poured onto ice water and the azidoderivative was collected by filtration, washed with cold water. Thesolid was dissolved in dichloromethane (200 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by silica gel chromatography(petroleum ether:ethyl acetate=10:1) to give the title compound. ¹H NMR(400 MHz, CDCl3) δ=8.04-7.95 (m, 1H), 7.37 (s, 1H), 7.26-7.20 (m, 2H),3.96 (s, 3H), 2.48-2.37 (m, 3H).

Step 4—Methyl 4-chloro-5-methyl-1H-indole-2-carboxylate

A solution of methyl(Z)-2-azido-3-(2-chloro-3-methyl-phenyl)prop-2-enoate (20.9 g, 83.2mmol) in toluene (250 mL) was heated to 120° C. under a nitrogen for 16hrs. On completion, the reaction mixture was concentrated to afford thecrude product as a yellow solid. The crude product was purified bysilica gel chromatography (petroleum ether:ethyl acetate=20:1) to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=12.21 (br. s., 1H), 7.34(d, J=8.3 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.3 Hz, 1H), 3.89(s, 3H), 2.40 (s, 3H).

Step 5—Methyl 4-chloro-1,5-dimethyl-1H-indole-2-carboxylate

To a solution of methyl 4-chloro-5-methyl-1H-indole-2-carboxylate (16.0g, 71.8 mmol) in DMF (300 mL) was added K₂CO₃ (9.93 g, 71.8 mmol) andMeI (30.4 g, 215 mmol) at rt. The reaction was stirred at 60° C. undernitrogen for 16 hrs. On completion, the reaction mixture was filteredand the filter cake was washed with dichloromethane (30 mL), thefiltrate was concentrated to afford the crude product. The crude productwas purified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.36(s, 1H), 7.28-7.19 (m, 2H), 4.07 (s, 3H), 3.94 (s, 3H), 2.49 (s, 3H).

Step 6—4-Chloro-1,5-dimethyl-1H-indole-2-carboxylic acid

To a solution of methyl 4-chloro-1,5-dimethyl-indole-2-carboxylate (11.0g, 46.4 mmol) in a mixture solvent of tetrahydrofuran (90 mL) and H₂O(30 ml) was added LiOH·H₂O (7.80 g, 186 mmol) at rt under nitrogen. Thereaction mixture was stirred at rt for 16 hrs. On completion, thereaction mixture was concentrated in vacuo, and the residue wasacidified with 2 N HCl (20 mL) to pH=3, and then was filtered. Thefilter cake was wash with water (20 mL), dried in vacuo to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ=13.14 (br. s., 1H), 7.49 (d,J=8.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.11 (s, 1H), 4.01 (s, 3H), 2.41(s, 3H).

4,5-Dichloro-6-methoxy-1-methyl-indole-2-carboxylic acid (IntermediateF)

Step 1—2,3-Dichloro-4-methoxy-benzaldehyde

To a solution of 1, 2-dichloro-3-methoxy-benzene (5.00 g, 28.2 mmol) indichloromethane (30 mL) was added TiCl₄ (9.11 g, 48.0 mmol) dropwise at0° C. under nitrogen. Then dichloro(methoxy)methane (3.25 g, 28.2 mmol)was added to the solution dropwise at 0° C. under nitrogen, and thesolution was stirred at rt for 5 hrs. The residue was poured into water(200 mL). The aqueous phase was extracted with ethyl acetate (3×300 mL).The combined organic phase was washed with brine (3×200 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=100:1 to 10:1) to give the title compound. ¹H-NMR (CD₃Cl₃, 400MHz): δ=10.36 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H),4.01 (s, 3H)

Step 2—Methyl(Z)-2-azido-3-(2,3-dichloro-4-methoxy-phenyl)prop-2-enoate

To a solution of sodium methoxide (7.90 g, 146 mmol) in methanol (300mL) was added 2,3-dichloro-4-methoxy-benzaldehyde (10.0 g, 48.8 mmol)several portions at −20° C. under nitrogen, then ethyl 2-azidoacetate(18.9 g, 146.3 mmol) was added to the solution dropwise at −20° C. undernitrogen. The mixture was stirred at rt for 12 hrs. The mixture waspoured into water (500 mL) and extracted with ethyl acetate (3×500 mL).The combined organic phase was washed with saturated brine (3×500 mL),dried over anhydrous sodium methoxide, filtered and concentrated invacuo. The residue was purified by column chromatography (petroleumether:ethyl acetate=100:1 to 1:1) to give the title compound. ¹H NMR(400 MHz, CDCl3) δ=8.19 (d, J=8.8 Hz, 1H), 7.29 (d, J=3.5 Hz, 1H), 6.93(d, J=9.0 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

Step 3—Methyl4,5-dichloro-6-methoxy-1H-indole-2-carboxylate

Methyl (Z)-2-azido-3-(2,3-dichloro-4-methoxy-phenyl)prop-2-enoate (500mg, 1.66 mmol) was added to xylene (100 mL) in one portion at rt, thesolution was stirred at 120° C. for 12 hrs. The mixture was concentratedin vacuo. The residue was washed with (petroleum ether:ethylacetate=10:1, 50 mL) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=12.31 (br. s., 1H), 7.07 (d, J=1.3 Hz, 1H), 7.01 (s, 1H),3.91 (s, 3H), 3.88 (s, 3H).

Step 4—4,5-Dichloro-6-methoxy-1-methyl-indole-2-carboxylate

To a solution of methyl 4,5-dichloro-6-methoxy-1H-indole-2-carboxylate(220 mg, 803 umol) in N,N-dimethylformamide (5 mL) was added potassiumcarbonate (333 mg, 2.41 mmol) and methyl iodide (342 mg, 2.41 mmol) inone portion at rt under nitrogen. The mixture was stirred at 50° C. for12 hrs. The mixture was then poured into water (10 mL). The aqueousphase was extracted with ethyl acetate (3×20 mL) the combined organicphase was washed with brine (3×20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound.¹H-NMR (DMSO-d6, 400 MHz): δ=7.31 (s, 1H), 7.15 (s, 1H), 4.03 (s, 3H),3.97 (s, 3H), 3.86 (s, 3H).

Step 5—4,5-Dichloro-6-methoxy-1-methyl-indole-2-carboxylic acid

To a solution of methyl4,5-dichloro-6-methoxy-1-methyl-indole-2-carboxylate (200 mg, 694 umol)in a mixture solvent of tetrahydrofuran (10 mL) and water (10 mL) wasadded lithium hydroxide (49.8 mg, 2.08 mmol) in one portion at rt undernitrogen. The mixture was stirred at rt for 12 hrs. The mixture wasconcentrated in vacuo, the residue was adjusted to pH=0.3 with 3Nhydrochloric acid (3 mL). The solid was filtered and concentrated invacuum to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=12.90(br. s., 1H), 7.29 (s, 1H), 7.10 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H).

4-Chloro-6-methoxy-1-methyl-indole-2-carboxylic acid (Intermediate G)

Step 1—Methyl (Z)-2-azido-3-(2-chloro-4-methoxy-phenyl)prop-2-enoate

To a mixture of sodium methoxide (950 mg, 17.6 mmol) in methanol (10 mL)was added 2-chloro-4-methoxy-benzaldehyde (1.00 g, 5.86 mmol) and ethyl2-azidoacetate (2.27 g, 17.6 mmol) in methanol (10 mL) dropwise at −40°C. under nitrogen. The mixture was stirred at −40° C. for 30 minutes,then the mixture was warmed to rt and stirred for 1.5 hours. Oncompletion, the reaction was poured into water (50 mL) and the reactionwas filtrated and the filter cake was dried in vacuo to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=8.39-8.15 (m, 1H), 7.43-7.16 (m,1H), 7.09-6.15 (m, 2H), 3.95 (s, 3H), 3.88 (s, 3H).

Step 2—Methyl 4-chloro-6-methoxy-1H-indole-2-carboxylate

Methyl (Z)-2-azido-3-(2-chloro-4-methoxy-phenyl)prop-2-enoate (440 mg,1.64 mmol) was dissolved in xylene (10 mL) under nitrogen. The mixturewas heated to 140° C. and stirred for 1 hour. On completion, thereaction was concentrated in vacuo to give the title compound (370 mg,crude) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.96 (s, 1H), 7.28 (s,1H), 6.88 (s, 1H), 6.76 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H).

Step 3—Methyl 4-chloro-6-methoxy-1-methyl-indole-2-carboxylate

To a mixture of methyl 4-chloro-6-methoxy-1H-indole-2-carboxylate (250mg, 1.04 mmol) and potassium carbonate (431 mg, 3.12 mmol) inN,N-dimethylformamide (5 mL) was added methyl iodide (738 mg, 5.20 mmol)in one portion at rt under nitrogen. The mixture was stirred at rt for30 minutes, then the mixture was heated to 60° C. and stirred for 1.5hours. On completion, the reaction was poured into water (15 mL) and wasstirred for 10 minutes. The reaction was filtrated and the solid wasdried in vacuo to give the title compound. ¹H NMR (400 MHz, DMSO-d6)δ=7.12 (s, 1H), 7.10 (s, 1H), 6.91 (s, 1H), 3.99 (s, 3H), 3.85 (s, 3H),3.83 (s, 3H).

Step 4—4-Chloro-6-methoxy-1-methyl-indole-2-carboxylic acid

To a mixture of methyl 4-chloro-6-methoxy-1-methyl-indole-2-carboxylate(90.0 mg, 355 umol) in tetrahydrofuran (1 mL) and water (1 mL) was addedlithium hydroxide (68.0 mg, 2.84 mmol) in one portion at rt undernitrogen. The mixture was stirred at rt and stirred for 2 hours. Thereaction was concentrated in vacuo. On completion, the residue waspoured into water (10 mL) and acidified by 2 N hydrochloric acid (2 mL)to pH=1-2. The mixture was filtrated and the solid was dried in vacuo togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=240.1, tR=0.804.

4,5-Dichloro-6-hydroxy-1-methyl-indole-2-carboxylic acid (IntermediateH)

Step 1—Methyl 4,5-dichloro-6-hydroxy-1-methyl-indole-2-carboxylate

To a solution of methyl4,5-dichloro-6-methoxy-1-methyl-indole-2-carboxylate (1.60 g, 5.55 mmol)in dichloromethane (20 mL) was added boron tribromide (2.78 g, 11.1mmol, 1.07 mL) at 0° C., then the mixture was stirred at rt for 16hours. On completion, the mixture was diluted with dichloromethane (20mL), then the solution was poured into water (30 mL). The mixture wasfiltered and the filtrate was extracted with dichloromethane (3×30 mL).The combined organic phase was concentrated, and the residue wascombined with filter cake and dried in vacuo to give a mixture of4,5-dichloro-6-hydroxy-1-methyl-1H-indole-2-carboxylic acid and itsmethyl ester.

To a solution of a mixture of4,5-dichloro-6-hydroxy-1-methyl-1H-indole-2-carboxylic acid and itsmethyl ester (0.44 g, 5.54 mmol) in methanol (20 mL) was added thionylchloride (725 mg, 6.09 mmol) at rt, then the mixture was stirred at 50°C. for 16 hours. On completion, the mixture was concentrated in vacuoand the residue was triturated with methanol (10 mL); the mixture wasfiltered to get the filter cake and the filter cake was dried in vacuoto give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=10.71 (br. s.,1H), 7.10 (s, 1H), 6.98 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H).

Step 2—4,5-Dichloro-6-hydroxy-1-methyl-indole-2-carboxylic acid

To a solution of methyl4,5-dichloro-6-hydroxy-1-methyl-indole-2-carboxylate (500 mg, 1.82 mmol)in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide(130 mg, 5.46 mmol). The mixture was stirred at rt for 16 hours. Oncompletion, the mixture was diluted with water (10 mL) and extractedwith ethyl acetate (2×20 mL). The aqueous phase was adjusted to pH=4-5with hydrochloric acid (2 N) and filtered to get the filter cake. Thefilter cake was dried in vacuo to give the title compound. ¹H NMR (300MHz, DMSO-d6) δ=13.00 (br. s., 1H), 10.66 (s, 1H), 7.08 (s, 1H), 6.99(s, 1H), 3.98 (s, 3H).

4-Chloro-6-hydroxy-1-methyl-indole-2-carboxylic acid (Intermediate I)

Step 1—4-Chloro-6-hydroxy-1-methyl-indole-2-carboxylic acid

To a mixture of methyl 4-chloro-6-methoxy-1-methyl-indole-2-carboxylate(400 mg, 1.58 mmol) in dichloromethane (30 mL) was added borontribromide (3.96 g, 15.8 mmol) in one portion at 0° C. under nitrogen.The mixture was stirred at 0° C. for 30 min, then at rt for 15.5 hours.On completion, the reaction was poured into saturated aqueous sodiumbicarbonate (200 mL) and acidified with concentrated hydrochloric aciduntil pH=1-2. The reaction was concentrated in vacuo. The mixture wasfiltrated and the aqueous phase was extracted with dichloromethane (3×10mL). The organic layer was combined and concentrated in vacuo to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=12.83 (br s, 1H), 9.99(s, 1H), 7.05 (s, 1H), 6.80-6.75 (m, 2H), 3.90 (s, 3H).

Step 2—Methyl 4-chloro-6-methoxy-1H-indole-2-carboxylate

To a mixture of 4-chloro-6-hydroxy-1-methyl-indole-2-carboxylic acid(400 mg, 1.77 mmol) in methanol (15 mL) was added thionyl chloride (422mg, 3.55 mmol) at rt under nitrogen. The mixture was stirred at rt for30 min, then at 62° C. for 15.5 hrs. On completion, the reaction wasconcentrated in vacuo to give the title compound.

Step 3—4-Chloro-6-hydroxy-1-methyl-indole-2-carboxylic acid

To a mixture of methyl 4-chloro-6-hydroxy-1-methyl-indole-2-carboxylate(400 mg, 1.67 mmol) in tetrahydrofuran (10 mL) and water (5 mL) wasadded lithium hydroxide (160 mg, 6.68 mmol) in one portion at rt. Themixture was stirred at rt for 30 min, then at 50° C. for 2.5 hrs. Oncompletion, the mixture was concentrated in vacuo to remove the organicsolvent. The aqueous phase was acidified with hydrochloric acid (2 N)until pH=1-2. The solid was collected by filtration, and dried in vacuoto give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=12.86 (br s,1H), 9.90 (s, 1H), 7.05 (s, 1H), 6.78-6.76 (m, 2H), 3.90 (s, 3H).

9-Chloro-6-methyl-3,6-dihydro-2H-[1,4]dioxino[2,3-f]indole-7-carboxylicacid (Intermediate J)

Step 1—(Z)-Methyl 2-azido-3-(2-chloro-3,4-dimethoxy-phenyl)prop-2-enoate

To a solution of sodium methoxide (6.46 g, 120 mmol) in methanol (100mL) was added a mixture of 2-chloro-3,4-dimethoxy-benzaldehyde (8.00 g,40.0 mmol) and methyl 2-azidoacetate (13.8 g, 120 mmol) in methanol (100mL) at −40° C. The mixture was stirred from −40° C. to rt in 2 hours andthen at rt for 3 hours. On completion, the mixture was poured into water(50 mL) where a solid formed. The solid was collected by filtration,washed with methanol (50 mL) to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ=8.02 (d, J=9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.13 (s,1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.76 (s, 3H).

Step 2—Methyl 4-chloro-5,6-dimethoxy-1H-indole-2-carboxylate

A solution of methyl(Z)-2-azido-3-(2-chloro-3,4-dimethoxy-phenyl)prop-2-enoate (4.00 g, 13.4mmol) in toluene (60 mL) was stirred at 110° C. for 2 hours. Oncompletion, the reaction mixture was concentrated. The residue wastriturated with toluene (20 mL) to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=270.1, tR=0.782.

Step 3—Methyl 4-chloro-5,6-dimethoxy-1-methyl-indole-2-carboxylate

To the solution of methyl 4-chloro-5,6-dimethoxy-1H-indole-2-carboxylate(1.20 g, 4.45 mmol) and potassium carbonate (922 mg, 6.67 mmol) inN,N-dimethylformamide (8 mL) was added methyl iodide (1.89 g, 13.4mmol). The reaction mixture was stirred at 60° C. for 12 hours. Oncompletion, the mixture was poured into water (20 mL), where a solidformed. The solid was collected by filtration to give the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ=7.19 (s, 1H), 7.12 (s, 1H), 4.01(s, 3H), 3.94 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H).

Step 4—Methyl 4-chloro-5,6-dihydroxy-1-methyl-indole-2-carboxylate

To the solution of methyl4-chloro-5,6-dimethoxy-1-methyl-indole-2-carboxylate (500 mg, 1.76 mmol)in dichloromethane (15 mL) was added tribromoborane (4.41 g, 17.6 mmol)at −78° C. The reaction mixture was stirred from −78° C. to rt in 2hours, then at rt for 3 hours. On completion, the mixture was pouredinto water (20 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by chromatography (petroleumether:ethyl acetate=4:1) to give the title product. ¹H NMR (400 MHz,DMSO-d6) δ=10.08 (s, 1H), 8.94 (s, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 3.90(s, 3H), 3.82 (s, 3H).

Step 5—Methyl9-chloro-6-methyl-3,6-dihydro-2H-[1,4]dioxino[2,3-f]indole-7-carboxylate

To the solution of methyl4-chloro-5,6-dihydroxy-1-methyl-indole-2-carboxylate (380 mg, 1.49 mmol)in N,N-dimethylformamide (3 mL) was added 1,2-dibromoethane (335 mg,1.78 mmol) and cesium carbonate (1.45 g, 4.46 mmol). The reactionmixture was stirred at 70° C. for 2 hrs. On completion, the mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography(petroleum ether:ethyl acetate=8:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=282.0, tR=0.898.

Step6—9-Chloro-6-methyl-3,6-dihydro-2H-[1,4]dioxino[2,3-f]indole-7-carboxylicacid

To the solution of methyl9-chloro-6-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]indole-7-carboxylate(100 mg, 355 umol) in tetrahydrofuran (10 mL) and water (3 mL) was addedlithium hydroxide (17.0 mg, 710 umol). The reaction mixture was stirredat 60° C. for 4 hrs. On completion, the mixture was concentrated invacuo to remove the organic solvent, and then acidified by hydrochloricacid (2 N). The solid was collected by filtration, washed with water (5mL) to give the title product. ¹H NMR (400 MHz, DMSO-d6) δ=12.92 (br.s., 1H), 7.09 (s, 1H), 7.03 (s, 1H), 4.37-4.29 (m, 4H), 3.93 (s, 3H).

Methyl 4-chloro-5-hydroxy-1-methyl-indole-2-carboxylate (Intermediate K)

Step 1—Methyl-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate

To a solution of sodium thiomethoxide (9.50 g, 175 mmol) in methanol(100 mL) was added dropwise a solution of2-chloro-3-methoxy-benzaldehyde (10.0 g, 58.6 mmol) and ethyl2-azidoacetate (22.7 g, 175 mmol) in methanol (100 mL) at −40° C. Afterthe reaction mixture was stirred at −50° C. for 2 hr, it was warmed tort during 2 hrs. The reaction mixture was then stirred at rt for 14 hrs.On completion, the mixture was poured into ice water (300 mL) andextracted with dichloromethane (2×200 mL), the combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give a residue. The residue was purified with silica gelchromatography (petroleum ether:ethyl acetate=20:1) to afford the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=7.77 (dd, J=1.0, 8.0 Hz, 1H), 7.36(s, 1H), 7.32-7.25 (m, 1H), 6.95 (dd, J=1.2, 8.2 Hz, 1H), 3.96 (s, 3H),3.94 (s, 3H).

Step 2—Methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate

A solution of methyl-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate(10.0 g, 37.3 mmol) in xylene (150 mL) was stirred at 160° C. for 5 hrs.On completion, the mixture was concentrated in vacuo to give a residue.The residue was triturated with a mixture of petroleum ether (100 mL),dichloromethane (5 mL) and methanol (5 mL) to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ=12.16 (br. s., 1H), 7.40 (dd, J=0.6, 9.0 Hz,1H), 7.24 (d, J=9.0 Hz, 1H), 7.04 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H).

Step 3—Methyl 4-chloro-5-methoxy-1-methyl-indole-2-carboxylate

To a mixture of methyl 4-chloro-5-methoxy-1H-indole-2-carboxylate (7.34g, 30.6 mmol) and potassium carbonate (16.9 g, 122 mmol) in N,N-dimethylformamide (80 mL) was added methyl iodide (21.7 g, 153 mmol),and the mixture was stirred at 60° C. for 16 hrs. On completion, thereaction mixture was filtered; the filtrate was washed with water (100mL), extracted with ethyl acetate (2×100 mL). The combined organic layerwas dried over anhydrous sodium sulfate, concentrated in vacuo to affordthe title compound. ¹H NMR (400 MHz, CDCl3) δ=7.34 (s, 1H), 7.27 (d,J=9.0 Hz, 1H), 7.14 (d, J=9.0, 1H), 4.07 (s, 3H), 3.97 (s, 3H), 3.94 (s,3H).

Step 4—Methyl 4-chloro-5-hydroxy-1-methyl-indole-2-carboxylate

To a solution of methyl 4-chloro-5-methoxy-1-methyl-indole-2-carboxylate(3.00 g, 11.8 mmol) in dichloromethane (40 mL) was added a solution ofboron tribromide (23.7 g, 94.6 mmol) in dichloromethane (40 mL) dropwiseat −50° C. The mixture was stirred at −50° C. for 2 hrs and then wasallowed to warmed to rt and stirred 15 hrs. On completion, methanol (15mL) was added dropwise into the mixture at 0° C. The mixture wasconcentrated in vacuo, washed with water (20 mL), extracted with ethylacetate (3×30 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo togive 3 g of mixture of methyl4-chloro-5-hydroxy-1-methyl-indole-2-carboxylate and4-chloro-5-hydroxy-1-methyl-indole-2-carboxylic acid as yellow solid. Tothis crude solid in methanol (40 mL) was added sulfur dichloride (8.20g, 68.9 mmol) dropwise at 100° C. The resulting mixture was stirred at100° C. for 15 hrs. On completion, the mixture was concentrated in vacuoto give a residue. The residue was triturated in petroleum ether (50 mL)to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=9.69 (s, 1H),7.43 (d, J=8.7 Hz, 1H), 7.11-7.05 (m, 2H), 3.99 (s, 3H), 3.86 (s, 3H).

4-Chloro-5-cyclopropyl-1-methyl-1H-indole-2-carboxylic acid(Intermediate L)

Step 1—Methyl4-chloro-1-methyl-S-(((trifluoromethyl)sulfonyl)oxy)-1H-indole-2-carboxylate

To a mixture of methyl 4-chloro-5-hydroxy-1-methyl-indole-2-carboxylate(1.00 g, 4.17 mmol) and pyridine (495 mg, 6.26 mmol) in dichloromethane(10 mL) was added trifluoromethanesulfonic anhydride (1.30 g, 4.59mmol). The reaction mixture was stirred at rt for 12 hrs. On completion,the mixture was concentrated. The residue was purified by chromatography(petroleum ether:ethyl acetate=15/1) to give the title compound. ¹H NMR(400 MHz, DMSO-d6) δ=7.81 (d, J=9.0 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H),7.33 (s, 1H), 4.08 (s, 3H), 3.90 (s, 3H).

Step 2—Methyl 4-chloro-5-cyclopropyl-1-methyl-1H-indole-2-carboxylate

A mixture of methyl4-chloro-1-methyl-5-(trifluoromethylsulfonyloxy)indole-2-carboxylate(500 mg, 1.35 mmol), cyclopropylboronic acid (406 mg, 4.72 mmol),Pd(PPh₃)₄ (156 mg, 135.00 umol) and cesium carbonate (880 mg, 2.70 mmol)in dioxane (15 mL) and water (3 mL) was stirred at 100° C. for 2 hrs. Oncompletion, the mixture was concentrated. The residue was purified bychromatography (petroleum ether:ethyl acetate=60:1) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=264.2, tR=1.009.

Step 3—4-Chloro-5-cyclopropyl-1-methyl-1H-indole-2-carboxylic acid

To the solution of methyl4-chloro-5-cyclopropyl-1-methyl-indole-2-carboxylate (180 mg, 683 umol)in tetrahydrofuran (10 mL) and water (3 mL) was added lithium hydroxide(49.0 mg, 2.05 mmol). The mixture was stirred at 60° C. for 12 hrs. Oncompletion, the mixture was concentrated to remove the organic solventand the aqueous phase was acidified with hydrochloric acid (2 N). Thesolid that formed was then collected by filtration and washed with water(5 mL) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=248.0,tR=0.839.

4-chloro-6-methoxy-1,5-dimethyl-indole-2-carboxylic acid (IntermediateM)

Step 1—2-Chloro-4-methoxy-3-methyl-benzaldehyde

To a solution of 1-chloro-3-methoxy-2-methyl-benzene (6.20 g, 39.6 mmol)in dichloromethane (60 mL) was added TiCl₄ (12.7 g, 67.3 mmol) dropwiseat 0° C. under nitrogen. Then dichloro(methoxy)methane (4.55 g, 39.6mmol) was added to the solution dropwise at 0° C. under nitrogen, andthe solution was stirred at rt for 5 hrs. On completion, the reactionwas poured into water (200 mL). The aqueous phase was extracted withethyl acetate (3×300 mL). The combined organic phase was washed withbrine (3×200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=100:1 to 10:1) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d6): δ=10.24 (s, 1H), 7.78-7.76(d, J=8.8 Hz, 1H), 7.16-6.14 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.25 (s,3H).

Step 2—Methyl(Z)-2-azido-3-(2-chloro-4-methoxy-3-methyl-phenyl)prop-2-enoate

To a solution of sodium methoxide (4.39 g, 81.3 mmol) in methanol (300mL) was added 2-chloro-4-methoxy-3-methyl-benzaldehyde (5.00 g, 27.1mmol) in several portions at −20° C. under nitrogen. Then ethyl2-azidoacetate (10.5 g, 81.3 mmol) was added to the solution dropwise at−20° C. under nitrogen. The mixture was stirred at rt for 12 hrs. Oncompletion, the mixture was poured into water (500 mL) and extractedwith ethyl acetate (3×500 mL). The combined organic phase was washedwith saturated brine (3×500 mL), dried over anhydrous sodium methoxide,filtered and concentrated in vacuo. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=100:1 to 1:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=282.02, tR=0.998.

Step 3—Methyl 4-chloro-6-methoxy-5-methyl-1H-indole-2-carboxylate

Methyl (Z)-2-azido-3-(2-chloro-4-methoxy-3-methyl-phenyl) prop-2-enoate(4.00 g, 14.2 mmol) was added to xylene (100 mL) in one portion at rt,then the solution was stirred at 120° C. for 12 hrs. The mixture wasconcentrated in vacuo. The residue was washed with (petroleumether:ethyl acetate=10:1, 50 mL) to give the title compound. ¹H-NMR(DMSO-d₆, 400 MHz): δ=12.02 (br. s., 1H), 7.01 (s, 1H), 6.86 (s, 1H),3.86 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H).

Step 4—Methyl 4-chloro-6-methoxy-1,5-dimethyl-indole-2-carboxylate

To a solution of methyl4-chloro-6-methoxy-5-methyl-1H-indole-2-carboxylate (3.00 g, 11.8 mmol)in N,N-dimethylformamide (10 mL) was added potassium carbonate (4.90 g,35.5 mmol) and methyl iodide (5.04 g, 35.5 mmol) in one portion at rtunder nitrogen. The mixture was stirred at 50° C. for 12 hrs. Oncompletion, the residue was poured into water (10 mL). The aqueous phasewas extracted with ethyl acetate (3×20 mL). The combined organic phasewas washed with brine (3×20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=268.07, tR=0.778.

Step 5—4-chloro-6-methoxy-1,5-dimethyl-indole-2-carboxylic acid

To a solution of methyl4-chloro-6-methoxy-1,5-dimethyl-indole-2-carboxylate (3.00 g, 11.2 mmol)in a mixture solvent of tetrahydrofuran (10 mL) and water (10 mL) wasadded lithium hydroxide (269 g, 11.2 mmol) in one portion at rt undernitrogen. The mixture was stirred at rt for 12 hrs. On completion, themixture was concentrated in vacuo, and the residue was adjusted topH=0.3 with 3N hydrochloric acid (3 mL). The solid was filtered andconcentrated in vacuum to give the title compound. ¹H NMR (400 MHz,DMSO-d6) δ=7.06 (s, 2H), 3.99 (s, 3H), 3.90 (s, 3H), 2.26 (s, 3H).

4-Chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxylic acid(Intermediate N)

Step 1—2-Chloro-3-fluoro-4-methoxybenzaldehyde

To a mixture of 1-chloro-2-fluoro-3-methoxy-benzene (5.00 g, 31.1 mmol)in dichloromethane (40 mL) was added titanium tetrachloride (10.0 g,52.9 mmol) dropwise at 0° C. under a nitrogen. Dichloro(methoxy)methane(3.58 g, 31.1 mmol) was then added to the solution. Then the mixture wasstirred at rt for 3 hours. On completion, the residue was poured intoice-water (50 mL) and extracted with ethyl acetate (50 mL). The combinedorganic layer was washed with brine (50 mL), dried with anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography eluted with (petroleum ether/ethylacetate=20/1 to 3/1) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=10.15 (s, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.37 (d, J=5.9 Hz,1H), 3.98 (s, 3H).

Step 2—(Z)-methyl 2-azido-3-(2-chloro-3-fluoro-4-methoxyphenyl)acrylate

To a solution of sodium methoxide (1.72 g, 31.8 mmol) in methanol (25mL) was added a solution of 2-chloro-3-fluoro-4-methoxy-benzaldehyde(2.00 g, 10.6 mmol) and ethyl azidoacetate (4.11 g, 31.8 mmol) inmethanol (25 mL) at −20° C. under nitrogen. The mixture was stirred atrt for 5 hours. On completion, the mixture was poured into ice-water (50mL) and a large amount of precipitate formed. The solution was filteredand the filter cake collected. The filter cake was then dissolved indichloromethane and dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ=8.09 (dd, J=9.0, 1.9 Hz, 1H), 7.27 (t, J=8.8 Hz,1H), 7.05 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H).

Step 3—Methyl 4-chloro-5-fluoro-6-methoxy-1H-indole-2-carboxylate

(Z)-methyl-2-azido-3-(2-chloro-3-fluoro-4-methoxy-phenyl)prop-2-enoate(1.80 g, 6.30 mmol) was added to xylene (20 mL) in one portion at rt.The solution was stirred at 180° C. for 2.5 hours. On completion, theresidue was cooled where a precipitation formed. The solution wasfiltered to give the crude compound. The crude product was used directlyin the next step without further purification.

Step 4—Methyl4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxylate

To a solution of methyl4-chloro-5-fluoro-6-methoxy-1H-indole-2-carboxylate (1.00 g, 3.88 mmol)in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.61 g,11.6 mmol) and iodomethane (1.65 g, 11.6 mmol) in one portion at rtunder nitrogen, and the mixture was stirred at 50° C. for 4 hours. Oncompletion, the residue was poured into ice-water (50 mL). The aqueouslayer was extracted with ethyl acetate (50 mL) and combined organiclayer was washed with brine (30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound.¹H NMR (400 MHz, DMSO-d₆) δ=7.31 (d, J=6.8 Hz, 1H), 7.14 (s, 1H), 4.01(s, 3H), 3.96 (s, 3H), 3.85 (s, 3H).

Step 5—4-Chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxylic acid

To a solution of methyl4-chloro-5-fluoro-6-methoxy-1-methyl-1H-indole-2-carboxylate (1.00 g) inanhydrous tetrahydrofuran (20.00 mL) and water (20.00 mL) was addedlithium hydroxide (264 mg, 11.0 mmol) in one portion at rt undernitrogen. The solution was stirred for 2 hours at rt. On completion, themixture was concentrated in vacuo to remove the tetrahydrofuran, thenthe residue was adjusted to pH=2 with hydrochloric acid (3 M) and aprecipitate emerged. The solid was filtered and dried in vacuo to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.31 (d, J=6.6 Hz, 1H),7.13 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H).

N-acetylsulfamoyl chloride (Intermediate O)

To a solution of N-(oxomethylene)sulfamoyl chloride (70.0 g, 495 mmol)in dichloromethane (50 mL) was added acetic acid (29.7 g, 495 mmol)dropwise at 0° C. The reaction was stirred at 0° C. for 3 hrs. Oncompletion, the reaction was concentrated in vacuo, and the residue waswashed with (petroleum ether:ethyl acetate=10:1, 2×500 mL) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ=2.11 (s, 3H).

Tert-butyl chlorosulfonylcarbamate (Intermediate P)

A solution of N-(oxomethylene)sulfamoyl chloride (20 g, 141 mmol) indichloromethane (200 mL) was added dropwise into t-BuOH (13.8 g, 184mmol) at 0° C. under a nitrogen. The reaction mixture was stirred at 0°C. for 0.5 hr. On completion, the mixture was concentrated in vacuo togive a residue (the temperature during the concentration was kept below35° C.). The residue was triturated with a mixture solvent of petroleumether and ethyl acetate (10:1, 50 ml) and dried over in vacuo to affordthe title compound. ¹H NMR (400 MHz, CDCl3) δ=8.62 (br. s., 1H), 1.58(s, 9H).

Tert-butyl 4-amino-4-(3-bromophenyl) piperidine-1-carboxylate(Intermediate

Step 1—Tert-butyl 4-(3-bromophenyl)-4-cyanopiperidine-1-carboxylate

To a solution of tert-butyl N, N-bis(2-chloroethyl)carbamate (11.6 g,47.8 mmol, CAS #118753-70-1) and 2-(3-bromo-phenyl)acetonitrile (10.3 g,52.5 mmol) in N, N-dimethylformamide (46 mL) was added sodium hydride(4.40 g, 110 mmol) portion-wise at 0° C. under nitrogen gas atmosphere.The reaction mixture was then warmed to 60° C. and stirred for 3 hrs. Oncompletion, water was added to the mixture (200 mL) at rt, and themixture was extracted with ethyl acetate (3×200 mL). The combinedorganic phase was washed by brine (200 mL), dried over sodium sulfate,and concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) togive the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.62 (t, J=1.6 Hz,1H), 7.52-7.50 (m, 1H), 7.46-7.43 (m, 1H), 7.31 (t, J=8.0 Hz, 1H), 4.32(m, 2H), 3.21 (m, 2H), 2.11 (d, J=13.2 Hz, 2H), 1.94 (td, J=13.2, 4.4Hz, 2H), 1.51 (s, 9H).

Step 2—Tert-butyl 4-(3-bromophenyl)-4-carbamoylpiperidine-1-carboxylate

To a mixture of tert-butyl4-(3-bromophenyl)-4-cyano-piperidine-1-carboxylate (6.00 g, 16.4 mmol)and potassium carbonate (908 mg, 6.57 mmol) in dimethyl sulfoxide (60mL) was added hydrogen peroxide (7.08 g, 62.4 mmol) at rt. Then, themixture was heated to 60° C. and stirred for 3 hrs. On completion, water(100 mL) was added, during which a white solid precipitated. The mixturewas filtered, and the solid was collected and dried in vacuo to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ=7.52 (s, 1H), 7.45 (d, J=7.5Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.26 (m, 2H), 7.14 (s, 1H), 3.74 (d,J=13.2 Hz, 2H), 2.97 (br. s., 2H), 2.40 (d, J=13.2 Hz, 2H), 1.74-1.57(m, 2H), 1.39 (s, 9H)

Step 3—Tert-butyl 4-amino-4-(3-bromophenyl) piperidine-1-carboxylate

To a solution of tert-butyl4-(3-bromophenyl)-4-carbamoyl-piperidine-1-carboxylate (5.40 g, 14.1mmol) in acetonitrile (27 mL) and water (27 mL) was added PhI(CF₃CO₂)₂(6.66 g, 15.5 mmol) at rt. The mixture was heated to rt and stirred for16 hrs. On completion, ethyl acetate (50 mL) was added to the mixtureand the organic phase was separated. The organic phase was then washedby brine (30 mL), dried over sodium sulfate and concentrated in vacuo togive a residue which was purified by column chromatography (petroleumether:ethyl acetate=10:1 to 1:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ=7.74 (t, J=2.0 Hz, 1H), 7.51-7.48 (dd, J=7.6, 1H), 7.40(ddd, J=7.6, 2.0, 0.8 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 3.73 (d, J=8.8Hz, 2H), 3.41-3.26 (m, 4H), 1.77 (td, J=13.2, 4.4 Hz, 2H), 1.52 (d,J=12.4 Hz, 2H), 1.41 (s, 9H).

Tert-butyl 4-amino-4-phenyl-piperidine-1-carboxylate (Intermediate R)

To a solution of tert-butyl4-amino-4-(3-bromophenyl)piperidine-1-carboxylate (700 mg, 1.97 mmol) inmethanol (7 mL) was added Pd—C(10%, 0.15 g) under nitrogen gasatmosphere. The suspension was degassed under vacuum and purged withhydrogen gas several times. The mixture was stirred under hydrogen gas(35 psi) at rt for 3 hrs. On completion, the mixture was filtered, andthe filtrate was concentrated in vacuo to give the crude product whichwas used into the next step directly without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ=8.42 (br. s., 2H), 7.64 (d, J=7.2 Hz, 2H),7.56-7.39 (m, 3H), 3.80-3.63 (m, 2H), 3.01 (d, J=7.3 Hz, 2H), 2.42 (d,J=14.1 Hz, 2H), 2.08-1.92 (m, 2H), 1.40 (s, 9H).

Tert-butyl 4-(3-acetamidophenyl)-4-amino piperidine-1-carboxylate(Intermediate S)

To a 100 mL three-necked round-bottomed flask charged with a mixture oftert-butyl 4-amino-4-(3-bromophenyl)piperidine-1-carboxylate (1.00 g,2.81 mmol), acetamide (249 mg, 4.22 mmol), Pd₂(dba)₃ (257 mg, 281 umol),Xantphos (163 mg, 281 umol), and cesium carbonate (1.83 g, 5.62 mmol)was added N, N-dimethylformamide (10.0 mL) at rt. The resultant mixturewas flushed with nitrogen gas three times, and heated to 100° C. andstirred for 4 hrs. On completion, the mixture was concentrated in vacuoto give a residue, to which water (20 mL) was added. The resultingmixture was extracted with dichloromethane (3×50 mL). The combinedorganic phase was washed by brine (50 mL), dried over sodium sulfate,and concentrated in vacuo to give a crude which was purified by columnchromatography (petroleum ether:ethyl acetate=1:2 todichloro-methane:methanol=50:1 to 20:1) to give the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ=9.89 (br. s, 1H), 7.63 (s, 1H), 7.52-7.48 (m,1H), 7.26-7.20 (m, 2H) 3.68 (d, J=13.2 Hz, 2H), 3.40-3.10 (m, 4H), 2.02(s, 3H), 1.77 (td, J=13.2, 4.2 Hz, 2H), 1.53 (d, J=17.2 Hz, 2H), 1.41(s, 9H).

(±)-1-Benzyl-3-(3-bromophenyl)piperidin-3-amine (Intermediate T)

Step 1—(±)-1-Benzyl-3-(3-bromophenyl)piperidin-3-ol

To a solution of 1,3-dibromobenzene (6.30 g, 26.7 mmol) intetrahydrofuran (65 mL) was added n-BuLi (2.5 M, 10.6 mL) at −78° C. Themixture was stirred at −78° C. for 30 minutes, then1-benzylpiperidin-3-one (5.05 g, 26.7 mmol) was added dropwise at −78°C. The mixture was stirred at 0° C. for 4 hrs. On completion, thereaction mixture was quenched by addition of aqueous ammonium chloride(100 mL) at 0° C., then diluted with water (100 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withaqueous brine (2×100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) togive the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.68 (t, J=1.8 Hz,1H), 7.45-7.29 (m, 7H), 7.25-7.17 (m, 1H), 3.68-3.50 (m, 2H), 2.99-2.89(m, 1H), 2.72 (td, J=2.0, 11.0 Hz, 1H), 2.31 (d, J=11.0 Hz, 1H),2.14-2.05 (m, 1H), 2.04-1.90 (m, 1H), 1.85-1.64 (m, 3H).

Step 2—(±)-N-[1-benzyl-3-(3-bromophenyl)-3-piperidyl]acetamide

To a solution of (±)-1-benzyl-3-(3-bromophenyl)piperidin-3-ol (6.00 g,17.3 mmol) in acetonitrile (45 mL) was added concentrated sulfuric acid(27.6 g, 276 mmol, 15 mL) dropwise at 0° C. The mixture was stirred atrt for 12 hours. On completion, the reaction mixture was quenched byaddition of sodium hydroxide (2 N, 50 mL) at 0° C., then diluted withwater (200 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with aqueous sodium chloride (2×100 mL),dried over sodium chloride, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (petroleumether:ethyl acetate=5:1 to 1:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ=7.40 (t, J=1.8 Hz, 1H), 7.32-7.17 (m, 7H), 7.13-7.03 (m,1H), 6.42 (br. s., 1H), 3.52-3.36 (m, 2H), 2.84 (d, J=11.3 Hz, 1H),2.70-2.54 (m, 2H), 2.00-1.86 (m, 5H), 1.80-1.51 (m, 3H)

Step 3—(±)-1-Benzyl-3-(3-bromophenyl)piperidin-3-amine

A solution of (±)-N-[1-benzyl-3-(3-bromophenyl)-3-piperidyl]acetamide(4.10 g, 10.6 mmol) in hydrochloric acid (6 N, 50 mL) was stirred at120° C. for 12 hours. On completion, the reaction mixture was quenchedby addition of sodium hydroxide (1 N, 80 mL) at 0° C., then diluted withwater (500 mL) and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with aqueous sodium chloride (3×50 mL), driedover sodium sulfate, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (petroleumether:ethyl acetate=3:1 to dichloromethane:methanol=10:1) to give thetitle compound. ¹H NMR (400 MHz, CDCl3) δ=7.76 (t, J=1.8 Hz, 1H),7.53-7.48 (m, 1H), 7.40-7.31 (m, 5H), 7.30-7.24 (m, 1H), 7.24-7.17 (m,1H), 3.61-3.47 (m, 2H), 2.82 (d, J=9.7 Hz, 1H), 2.62 (d, J=10.9 Hz, 1H),2.39 (d, J=9.5 Hz, 1H), 2.12 (m, 1H), 1.95-1.75 (m, 2H), 1.69-1.59 (m,2H).

Benzyl 3-amino-3-phenylazetidine-1-carboxylate (Intermediate U)

Step 1—Benzyl3-(1,1-dimethylethylsulfinamido)-3-phenylazetidine-1-carboxylate

To the solution of benzyl3-tert-butylsulfinyliminoazetidine-1-carboxylate (1.00 g, 3.24 mmol, MDL#: MFCD27987040) in tetrahydrofuran (10 mL) was added phenyllithium (2 Min dibutyl ether, 2.43 mL) and the mixture was stirred at 0° C. for 2hrs. On completion, the mixture was quenched by saturated aqueousammonium chloride solution (10 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated to give the title compound, which was used fornext step directly. LCMS: (ES⁺) m/z (M+H)⁺=387.1, tR=0.886.

Step 2—Benzyl 3-amino-3-phenylazetidine-1-carboxylate

A solution of benzyl3-(tert-butylsulfinylamino)-3-phenyl-azetidine-1-carboxylate (600 mg,1.55 mmol) in hydrochloride/ethyl acetate (4 mL, 4 M) was stirred at rtfor 1 hr. On completion, the mixture was concentrated to give a residue.The residue was dissolved in water (5 mL), then extracted with ethylacetate (5 mL). The aqueous phase was separated, concentrated in vacuoto give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=283.1, tR=0.557.

(±)-1-Benzyl-3-phenyl-pyrrolidin-3-amine (Intermediate V)

Step 1—(±)-1-Benzyl-3-phenyl-pyrrolidin-3-ol

To a solution of 1-benzylpyrrolidin-3-one (6.00 g, 34.2 mmol) intetrahydrofuran (20 mL) was added bromo(phenyl)magnesium (3 M, 12.5 mL)dropwise at 0° C. The mixture was stirred at rt for 12 hrs. Oncompletion, the reaction was quenched with saturated ammonium chloride(20 mL), extracted with ethyl acetate (3×50 mL), washed with brine (3×30mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=5:1) to give the title compound. ¹H NMR (300 MHz,CDCl3) δ=7.46-7.38 (m, 2H), 7.32-7.22 (m, 5H), 7.21-7.12 (m, 3H), 3.67(s, 2H), 3.15-3.01 (m, 1H), 2.91 (d, J=9.6 Hz, 1H), 2.56 (d, J=9.4 Hz,1H), 2.47 (dt, J=6.2, 9.3 Hz, 1H), 2.36-2.23 (m, 1H), 2.20-2.07 (m, 1H).

Step 2—(±)-N-(1-benzyl-3-phenyl-pyrrolidin-3-yl)acetamide

To a solution of (±)-1-benzyl-3-phenyl-pyrrolidin-3-ol (2.00 g, 7.89mmol) in acetonitrile (12.5 g, 304 mmol) was added sulfuric acid (9.59g, 97.7 mmol) dropwise at 0° C., and the reaction was stirred at rt for12 hrs. On completion the solution was poured into ice, basified withsodium hydroxide (5 N, 30 mL) and extracted with dichloromethane (3×50mL). The combined extracts were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1 to 1:1) to give thetitle compound. ¹H NMR (400 MHz, CDCl3) δ=7.45-7.15 (m, 10H), 3.83-3.60(m, 2H), 3.06-2.95 (m, 2H), 2.93-2.86 (m, 1H), 2.79-2.68 (m, 1H), 2.50(dt, J=3.3, 7.0 Hz, 2H), 2.02 (s, 3H)

Step 3—(±)-1-Benzyl-3-phenyl-pyrrolidin-3-amine

A mixture of (±)-N-(1-benzyl-3-phenyl-pyrrolidin-3-yl)acetamide (2.00 g,6.79 mmol) in hydrochloric acid (6 N, 50 mL) was stirred at 110° C. for8 hrs. On completion the mixture was poured into ice-water (20 mL),quenched by addition of saturated sodium bicarbonate (60 mL), andextracted with ethyl acetate (3×20 mL). The combined organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel (from petroleumether:ethyl acetate=10:1 to dichloromethane:methanol=10:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=253.2, tR=1.312.

2-Oxo-N-pyrimidin-2-yl-oxazolidine-3-sulfonamide (Intermediate W)

A 250 mL round-bottom flask was charged with dichloromethane (250 mL)and N-(oxomethylene) sulfamoyl chloride (14.9 g, 105 mmol). The flaskwas cooled in an ice bath for 20 minutes, and then 2-bromoethanol (13.1g, 105 mmol) was added dropwise. The mixture was stirred for 2.5 hours,then a solution of pyrimidin-2-amine (10 g, 105 mmol) and triethylamine(32 g, 317 mmol) in dichloromethane (150 mL) was added dropwise via anaddition funnel over 10 minutes. When the addition was complete, thecooling bath was removed, and the mixture was stirred for 2 days. Oncompletion, to the mixture was added 2N hydrochloric acid. Then themixture was filtered and the filter cake was washed with dichloromethaneand water. The solid was dried under vacuum to give the title compound.¹H NMR (400 MHz, DMSO-d₆) δ=8.66 (d, J=5.0 Hz, 2H), 7.30-6.99 (m, 1H),4.52-4.35 (m, 2H), 4.33-4.15 (m, 2H).

Tert-butyl 4-amino-4-(3-(ethoxycarbonyl)phenyl)piperidine-1-carboxylate(Intermediate X)

To a mixture of tert-butyl4-amino-4-(3-bromophenyl)piperidine-1-carboxylate (1.80 g, 5.07 mmol)and Pd(dppf)Cl₂—CH₂Cl₂ (414 mg, 507 umol) in ethanol (18.0 mL) was addedtriethylamine (2.57 g, 25.4 mmol) in one portion at rt under nitrogen.The mixture was flushed with carbon monoxide (50 psi) three times, thenheated to 85° C. and stirred for 16 hrs. On completion, the mixture wasfiltered, and the filtrate was concentrated in vacuo to give a residuewhich was purified by column chromatography (petroleum ether:ethylacetate=10:1 to 2:1) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=8.13 (s, 1H), 7.81 (dd, J=7.6, 1.6 Hz, 2H), 7.47 (t, J=8.0Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.75 (d, J=10.8 Hz, 2H), 3.19-3.28 (m,2H), 2.00 (br. s, 2H), 1.77-1.82 (m, 2H), 1.57 (d, J=12.4 Hz, 2H), 1.42(s, 9H), 1.33 (t, J=7.2 Hz, 3H).

Tert-butyl 4-amino-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate(Intermediate Y)

Step 1—Tert-butyl 4-(4-bromophenyl)-4-cyano-piperidine-1-carboxylate

To a solution of 2-(4-bromophenyl)acetonitrile (2.67 g, 13.6 mmol) andtert-butyl N,N-bis(2-chloroethyl)carbamate (3.00 g, 12.3 mmol) inN,N-dimethylformamide (20 mL) was added sodium hydride (1.14 g, 28.5mmol) portion-wise at 0° C. under a nitrogen atmosphere. After stirringat 0° C. for 0.5 hr, more N,N-dimethylformamide (20 mL) was added intothe mixture and the mixture was heated to 60° C. and stirred for 16 hrs.On completion, the mixture was quenched with ice water (150 mL) andextracted with ethyl acetate (2×200 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuumto give a residue. The residue was purified with silica gelchromatography (petroleum ether:ethyl acetate=20:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=7.47 (d, J=8.7 Hz, 2H), 7.28 (d,J=8.7 Hz, 2H), 4.41-4.00 (m, 2H), 3.25-3.05 (m, 2H), 2.00 (d, J=12.7 Hz,2H), 1.83 (dt, J=4.3, 13.1 Hz, 2H), 1.41 (s, 9H).

Step 2—Tert-butyl4-cyano-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-bromophenyl)-4-cyano-piperidine-1-carboxylate (2.60 g, 7.12 mmol)and Pd(dppf)Cl₂·CH₂Cl₂ (581 mg, 712 umol) in ethanol (30 mL) was addedtriethylamine (3.60 g, 35.6 mmol). The mixture was bubbled with carbonicoxide at 70° C. under 50 psi then stirred at 70° C. for 16 hrs. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified with silica gel chromatography (petroleumether:ethyl acetate=20:1) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=8.02 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 4.33 (q,J=7.2 Hz, 2H), 4.16 (d, J=14.2 Hz, 2H), 3.10-2.90 (m, 2H), 2.18-2.11 (m,2H), 2.04-1.90 (m, 2H), 1.43 (s, 9H), 1.33 (t, J=7.1 Hz, 3H).

Step 3—Tert-butyl4-carbamoyl-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-cyano-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate (2.30 g, 6.42mmol) and potassium carbonate (354 mg, 2.57 mmol) in dimethyl sulfoxide(25 mL) was added hydrogen peroxide (5.82 g, 51.3 mmol). The mixture washeated to 60° C. and stirred at 60° C. for 16 hrs. On completion, water(40 mL) was added into the mixture. After stirring at rt for 2 hrs asolid precipitate formed which was filtered. The solid was dried invacuo to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=7.93 (d,J=8.4 Hz, 2H), 7.55-7.51 (d, J=8.4 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.72(d, J=13.4 Hz, 2H), 3.10-2.94 (m., 2H), 2.43 (d, J=13.4 Hz, 2H),1.76-1.67 (m, 2H), 1.39 (s, 9H), 1.31 (t, J=7.1 Hz, 3H).

Step 4-Tert-butyl4-amino-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate

To a mixture of tert-butyl4-carbamoyl-4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate (1.34 g,3.56 mmol) in acetonitrile (5 mL) and water (5 mL) was addedPhI(O₂CCF₃)₂ (1.68 g, 3.92 mmol) in one portion and the mixture wasstirred at rt for 16 hrs. On completion, the mixture was concentrated invacuo to give a residue. The residue was extracted with ethyl acetate(3×40 mL), washed with water (30 mL) and the combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give a residue. The residue was purified with silica gelchromatograph (dichloromethane:methanol=40:1) to give the titlecompound. ¹H NMR (400 MHz, DMSO-d6) δ=8.48 (br. s., 2H), 8.07-8.01 (d,J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 3.77-3.62(m, 2H), 3.05 (m, 2H), 2.44 (d, J=14.8 Hz, 2H), 2.06-1.93 (m, 2H), 1.41(s, 9H), 1.34 (t, J=7.1 Hz, 3H).

(±)-1-Benzyl-3-(4-bromophenyl)piperidin-3-amine (Intermediate Z)

Step 1—(±)-1-Benzyl-3-(4-bromophenyl)piperidin-3-ol

To a solution of 1-bromo-4-iodo-benzene (3.30 g, 11.66 mmol) intetrahydrofuran (50 mL) was added n-BuLi (2.5 M, 4.99 mL) dropwise. Thereaction mixture was stirred at −60° C. for 1 hr. Then a solution of1-benzylpiperidin-3-one (2.21 g, 11.66 mmol) in tetrahydrofuran (10 mL)was added to the reaction mixture at −60° C. and the mixture was warmedto rt and stirred for 15 hrs. On completion, the reaction mixture wasquenched with saturated ammonium chloride solution (50 mL) at 0° C. andextracted with ethyl acetate (3×40 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtrated and concentrated in vacuoto give a crude product which was purified by column chromatography(petroleum ether:ethyl acetate=7:1 to 3:1) to give the title compound.¹H NMR (400 MHz, CDCl3) δ=7.50-7.25 (m, 9H), 3.97 (s, 1H), 3.69-3.53 (m,2H), 2.95 (d, J=10.42 Hz, 1H), 2.71 (d, J=11.04 Hz, 1H), 2.30 (d,J=11.04 Hz, 1H), 2.12-2.04 (m, 1H), 2.00-1.94 (m, 1H), 1.83-1.65 (m,3H).

Step 2—(±)-N-(1-benzyl-3-(4-bromophenyl)piperidin-3-yl)acetamide

To a solution of (±)-1-benzyl-3-(4-bromophenyl)piperidin-3-ol (1.05 g,3.03 mmol) in acetonitrile (20 mL) was added concentrated sulfuric acid(2.97 g, 30.32 mmol) at 0-rt. The reaction mixture was stirred for 48hrs. On completion, the reaction mixture was concentrated in vacuo. Theresidue was diluted with ethyl acetate (50 mL) and basified withsaturated sodium hydrogen carbonate solution (40 mL). Then the aqueousphase was extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtrated andconcentrated in vacuo to give a crude product which was purified bycolumn chromatography (petroleum ether:ethyl acetate=3:1 to 0:1) to givethe title compound. ¹H NMR (300 MHz, CDCl3) δ=7.48-7.16 (m, 9H), 6.51(br. s., 1H), 3.64-3.43 (m, 2H), 2.93 (d, J=11.11 Hz, 1H), 2.68 (d,J=11.49 Hz, 2H), 2.11-1.95 (m, 4H), 1.88-1.61 (m, 4H).

Step 3—(±)-1-Benzyl-3-(4-bromophenyl)piperidin-3-amine

A solution of (±)-N-[1-benzyl-3-(4-bromophenyl)-3-piperidyl]acetamide(1.05 g, 2.71 mmol) in hydrochloric acid solution (9 M, 13 mL) wasstirred at 120° C. for 24 hrs. On completion, the reaction mixture wasquenched with sodium bicarbonate solution until pH=8-9 at 0° C., and theaqueous phase was extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtrated andconcentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=7.38-7.13 (m, 9H), 3.45 (s, 2H), 2.73 (d, J=10.16 Hz, 1H), 2.53(d, J=10.79 Hz, 1H), 2.27 (d, J=10.42 Hz, 1H), 2.06-1.93 (m, 1H),1.87-1.67 (m, 5H), 1.55-1.48 (m, 1H).

Ethyl 4-(3-amino-1-benzylpiperidin-3-yl)benzoate (Intermediate AA)

To a solution of (±)-benzyl-3-(4-bromophenyl)piperidin-3-amine (650 mg,1.88 mmol) and triethylamine (951 mg, 9.40 mmol) in ethanol (20 mL) wasadded Pd(dppf)Cl₂—CH₂Cl₂ (153 mg, 188 umol) and the reaction mixture wasstirred at 80° C. for 24 hrs under carbon monoxide (50 psi). Oncompletion, the reaction mixture was concentrated in vacuo to give acrude product which was purified by column chromatography(dichloromethane:methanol=1:0 to 30:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=339.2.

(±)-Ethyl 3-(3-amino-1-benzyl-3-piperidyl)benzoate (Intermediate AB)

To a mixture of (±)-1-benzyl-3-(3-bromophenyl)piperidin-3-amine (500 mg,1.45 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (118 mg, 144 umol) in ethyl alcohol(18 mL) was added triethylamine (732.67 mg, 7.24 mmol) in one portion atrt under nitrogen. The mixture was stirred at 85° C. under carbonmonoxide (50 psi) for 12 hrs. On completion, the mixture wasconcentrated in vacuo and the residue was purified by chromatography onsilica gel (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=30:1) to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=339.2, tR=0.642.

(±)-3-(3-Bromophenyl)tetrahydrofuran-3-amine (Intermediate AC)

Step 1—(±)-3-(3-Bromophenyl)tetrahydrofuran-3-carbonitrile

To a solution of sodium hydride (1.84 g, 76.5 mmol) in dimethylformamide (30 mL) was added a solution of 2-(3-bromophenyl)acetonitrile(5.00 g, 25.5 mmol) and 1-chloro-2-(chloromethoxy)ethane (3.45 g, 26.7mmol) in dimethyl formamide (20 mL) at −20° C. under nitrogenatmosphere. The mixture was stirred at 20-25° C. for 16 hrs. Oncompletion, the mixture was poured into water (50 mL) and extracted withethyl acetate (2×60 mL). The combined organic phase was washed withbrine (100 mL) and concentrated to give the crude product, which waspurified by column chromatography (petroleum ether:ethyl acetate=50:1 to8:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.65 (t,J=1.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.48-7.41 (m, 1H), 7.34-7.26 (m, 1H),4.36 (d, J=9.0 Hz, 1H), 4.26-4.12 (m, 2H), 4.07 (d, J=9.0 Hz, 1H),2.87-2.77 (m, 1H), 2.46 (td, J=8.1, 13.1 Hz, 1H)

Step 2—(±)-3-(3-Bromophenyl)tetrahydrofuran-3-carboxamide

To a solution of (±)-3-(3-bromophenyl)tetrahydrofuran-3-carbonitrile(2.00 g, 7.93 mmol) and potassium carbonate (438 mg, 3.17 mmol) indimethyl sulfoxide (10 mL) was added hydrogen peroxide (3.43 g, 30.2mmol, 30%) in one portion at 20° C. Then the mixture was stirred at20-25° C. for 3 hrs. On completion, the mixture was diluted with water(20 mL) and extracted with ethyl acetate (2×20 mL). The combined organicphase washed with brine (30 mL) and concentrated to give the crudeproduct. The crude product was recrystallized by petroleum ether:ethylacetate=1:1 (10 mL) and filtered to give the title compound. ¹H NMR (400MHz, CDCl3) δ=7.48 (d, J=1.4 Hz, 1H), 7.47-7.39 (m, 1H), 7.32-7.24 (m,2H), 5.70 (br. s., 2H), 4.44 (d, J=8.9 Hz, 1H), 4.13-3.91 (m, 3H),2.89-2.73 (m, 1H), 2.37-2.22 (m, 1H).

Step 3—(±)-3-(3-Bromophenyl)tetrahydrofuran-3-amine

To a solution of (±)-3-(3-bromophenyl)tetrahydrofuran-3-carboxamide(1.85 g, 6.85 mmol) in acetonitrile (10 mL) and water (10 mL) was added[phenyl-(2,2,2-trifluoroacetyl)oxy-iodanyl]2,2,2-trifluoroacetate (3.24g, 7.53 mmol) at 20-25° C. The mixture was stirred at 20-25° C. for 12hrs under nitrogen atmosphere. On completion, the mixture was adjustedto pH=9-10 with ammonium hydroxide and concentrated to remove theacetonitrile. Then to the mixture was added water (10 mL) and thesolution was extracted with dichloromethane (2×10 mL). The combinedorganic phase was concentrated to give the title compound. ¹H NMR (400MHz, CDCl3) δ=7.66 (t, J=1.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.31-7.19 (m,1H), 4.24-4.15 (m, 1H), 4.10 (dt, J=4.0, 8.8 Hz, 1H), 3.95-3.83 (m, 2H),2.39 (td, J=8.8, 12.5 Hz, 1H), 2.20-2.11 (m, 1H).

(±)-3-(4-Bromophenyl)tetrahydrofuran-3-amine (Intermediate AD)

Step 1—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-carbonitrile

To a solution of sodium hydride (1.06 g, 44.3 mmol) in dimethylformamide (30 mL) was added a solution of1-chloro-2-(chloromethoxy)ethane (2.00 g, 15.5 mmol) and2-(4-bromophenyl)acetonitrile (2.90 g, 14.7 mmol) in dimethyl formamide(20 mL) dropwise at −20° C., and the reaction mixture was stirred at rtfor 16 hrs. On completion, the mixture was poured into water (80 mL) andextracted with ethyl acetate (3×60 mL). The combined organic phase waswashed with brine (3×70 mL) and concentrated in vacuo to give a crudeproduct which was purified by column chromatography (petroleumether:ethyl acetate=50:1-15:1) to give the title compound. ¹H NMR (300MHz, CDCl3) δ=7.56 (d, J=8.7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 4.35 (d,J=9.0 Hz, 1H), 4.24-4.13 (m, 2H), 4.04 (d, J=9.0 Hz, 1H), 2.82 (ddd,J=5.1, 7.2, 12.8 Hz, 1H), 2.43 (td, J=8.1, 13.0 Hz, 1H).

Step 2—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-carboxamide

To a solution of (±)-3-(4-bromophenyl)tetrahydrofuran-3-carbonitrile(900 mg, 3.57 mmol) and potassium carbonate (197 mg, 1.43 mmol, 0.40 eq)in dimethyl sulfoxide (10 mL) was added hydrogen peroxide (1.31 mL, 30%)dropwise at rt, and the reaction mixture was stirred at rt for 2 hrs. Oncompletion, the reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (3×20 mL). The combined organic phasewashed with brine (30 mL) and concentrated in vacuo to give a crudeproduct. The product was recrystallized by petroleum ether:ethylacetate=1:1 (10 mL) and filtered to give a residue and the residue wasdried in vacuo to give the title compound. ¹H NMR (300 MHz, CDCl3)δ=7.44 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 5.55-5.20 (m, 2H),4.36 (d, J=8.9 Hz, 1H), 4.08-3.82 (m, 3H), 2.82-2.69 (m, 1H), 2.22 (ddd,J=6.8, 8.2, 12.5 Hz, 1H).

Step 3—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-amine

To a solution of (±)-3-(4-bromophenyl)tetrahydrofuran-3-carboxamide (300mg, 1.11 mmol) in a mixture of acetonitrile (10 mL) and water (10 mL)was added [phenyl-(2,2,2-trifluoroacetyl)oxy-iodanyl]2,2,2-trifluoroacetate (525 mg, 1.22 mmol) at rt and the reactionmixture was stirred at rt for 12 hrs. On completion, the reactionmixture was adjusted to pH=9-10 with ammonium hydroxide and concentratedin vacuo to remove acetonitrile. Then to the mixture was added water (10mL) and the solution was extracted with ethyl acetate (2×10 mL). Thecombined organic phase was concentrated to give the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ=7.48 (q, J=8.7 Hz, 4H), 4.06-3.97 (m, 1H), 3.90(dt, J=4.0, 8.3 Hz, 1H), 3.74-3.66 (m, 2H), 2.17 (td, J=8.5, 12.2 Hz,1H), 2.09-1.94 (m, 1H).

(±)-Methyl 4-(3-aminooxetan-3-yl)benzoate (Intermediate AE)

Step 1—2-(±)-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide

To a solution of oxetan-3-one (2.50 g, 34.6 mmol) and(±)-2-methylpropane-2-sulfinamide (4.20 g, 34.6 mmol) in anhydroustetrahydrofuran (25 mL) was added tetraethoxytitanium (11.0 g, 48.5mmol, 10 mL) dropwise at rt and the reaction mixture was stirred at 50°C. for 3 hrs. On completion, the reaction mixture was poured into 100 mLcool water and filtered. The filtrate was extracted with dichloromethane(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The resulting solid waspurified by silica gel chromatography (petroleum ether:ethylacetate=20:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃)δ=5.83-5.76 (m, 1H), 5.70-5.62 (m, 1H), 5.52-5.40 (m, 2H), 1.27 (s, 9H).

Step2—(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide

To a solution of 1-bromo-4-iodo-benzene (806 mg, 2.85 mmol) in anhydroustetrahydrofuran (20 mL) was added n-BuLi (2.5 M, 1.14 mL) dropwise at−70° C. and the reaction mixture was stirred for 10 min under nitrogen.Then a solution of (±)-2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (500 mg, 2.85 mmol, CAS #1158098-73-7) inanhydrous tetrahydrofuran (5 mL) was added dropwise and the reactionmixture was stirred at −70° C. for 20 min. Then the reaction mixture wasstirred at rt for 30 min. On completion, the reaction mixture was pouredinto 100 mL cool water and the aqueous phase was extracted withdichloromethane (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. Theresulting oil was purified by silica gel chromatography (petroleumether:ethyl acetate=1:1) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=334.0, tR=1.195. ¹H NMR (400 MHz, CDCl₃) δ=7.48 (d, J=8.5 Hz,2H), 7.23-7.16 (d, J=8.5 Hz, 2H), 5.09 (d, J=6.9 Hz, 1H), 5.01-4.92 (m,2H), 4.89-4.83 (d, J=6.9 Hz, 1H), 4.02 (s, 1H), 1.14 (s, 9H).

Step 3—(±)-Methyl 4-[3-(tert-butylsulfinylamino)oxetan-3-yl]benzoate

A solution of(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide (500mg, 1.50 mmol), triethylamine (455 mg, 4.50 mmol, 623 uL) andPd(dppf)Cl₂·CH₂Cl₂ (244 mg, 300 umol) in a mixture of methanol (20 mL)and dimethyl sulfoxide (4 mL) was stirred at 80° C. under carbonmonoxide (50 psi) for 16 hrs. On completion, the reaction mixture wasconcentrated in vacuo. The resulting oil was purified by silica gelchromatography (dichloromethane:methanol=50:1) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=312.1, tR=1.065. ¹H NMR (400 MHz,CDCl₃) δ=8.12-8.07 (m, 2H), 7.51-7.46 (m, 2H), 5.22 (d, J=7.0 Hz, 1H),5.08-5.03 (m, 2H), 5.00-4.96 (m, 1H), 3.94 (s, 3H), 1.22 (s, 9H).

Step 4—(±)-Methyl 4-(3-aminooxetan-3-yl)benzoate

To a solution of (±)-methyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]benzoate (290 mg, 931 umol) ina mixture of tetrahydrofuran (1 mL) and water (300 uL) was added iodine(47.2 mg, 186 umol, 37.5 uL) and the reaction mixture was stirred at 50°C. for 12 hrs. On completion, the reaction mixture was concentrated invacuo. The resulting oil was basified with aqueous saturated sodiumbicarbonate until pH=9 and the aqueous phase was extracted withdichloromethane (3×30 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo to givethe title compound as black brown oil. LCMS: (ES⁺) m/z (M-NH2)⁺=191.1,tR=0.809.

(±)-Ethyl 4-(3-aminotetrahydro-2H-pyran-3-yl) benzoate (Intermediate AF)

Step 1—1-Chloro-3-(chloromethoxy)propane

To a solution of paraformaldehyde (6.0 g, 66.6 mmol) in dichloromethane(300 mL) was bubbled HCl (gas) at −10° C. until the solution becameclear. Then, 3-chloropropan-1-ol (18.9 g, 200 mmol, 16.7 mL) was addeddropwise and the reaction mixture was stirred at −10° C. for 10 mins. Oncompletion, the reaction was poured into a suspension of anhydrouspotassium carbonate (100 g) in dichloromethane (300 mL) and stirreduntil bubbling ceased. The reaction mixture was filtered andconcentrated in vacuo to give the desired product. ¹H NMR (400 MHz,DMSO-d6) δ=5.52 (s, 2H), 3.86 (t, J=6.0 Hz, 2H), 3.67-3.63 (m, 2H),2.14-2.07 (m, 2H).

Step 2—(±)-3-(4-Bromophenyl)tetrahydro-2H-pyran-3-carbonitrile

To a solution of sodium hydride (3.40 g, 85.3 mmol, 60% purity) inN,N-dimethylformamide (80 mL) was added a solution of2-(4-bromophenyl)acetonitrile (8.00 g, 40.8 mmol) and1-chloro-3-(chloromethoxy)propane (5.60 g, 39 mmol) inN,N-dimethylformamide (50 mL) portion-wise at −40° C. under nitrogen.The reaction mixture was warmed to rt with stirring for 12 hrs. Oncompletion, to the reaction mixture was added water (200 mL) and thesolution was extracted with ethyl acetate (3×100 mL). The organic layerswere washed with brine (200 mL), dried over anhydrous sodium sulfate,and concentrated in vacuo. The solid was purified by silica gelchromatography (petroleum: ethyl acetate=20:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=7.56 (d, J=8.4 Hz, 2H), 7.38 (d,J=8.4 Hz, 2H), 4.10 (dd, J=11.2, 2.4 Hz, 2H), 3.55 (d, J=11.4 Hz, 1H),3.53-3.45 (m, 1H), 2.33 (dd, J=11.2, 2.0 Hz, 1H), 2.26-2.15 (m, 1H),2.15-2.04 (m, 1H), 1.82-1.74 (m, 1H).

Step 3—(±)-3-(4-Bromophenyl)tetrahydro-2H-pyran-3-carboxamide

To a mixture of (±)-3-(4-bromophenyl)tetrahydropyran-3-carbonitrile(1.10 g, 4.20 mmol) and anhydrous potassium carbonate (235 mg, 1.70mmol) in dimethyl sulfoxide (5 mL) was added hydrogen peroxide (1.80 g,16.1 mmol, 1.5 mL, 30% purity) in one portion at rt. Then, the mixturewas heated to 60° C. and stirred for 3 hrs. On completion, the reactionmixture was diluted with water (20 mL) where a precipitate formed. Thewhite precipitated solid was filtered and dried in vacuo to give thetitle compound. ¹H NMR (400 MHz, DMSO-d6) δ=7.59 (d, J=8.4 Hz, 2H), 7.38(d, J=8.4 Hz, 2H), 7.23 (br. s., 1H), 7.11 (br. s., 1H), 4.28 (d, J=11.4Hz, 1H), 3.78 (d, J=11.8 Hz, 1H), 3.74-3.66 (m, 1H), 3.54-3.47 (m, 1H),2.50-2.41 (m, 1H), 2.03-1.90 (m, 1H), 1.70-1.59 (m, 1H), 1.51 (m, 1H)

Step 4—(±)-3-(4-Bromophenyl)tetrahydro-2H-pyran-3-amine

To a solution of (±)-3-(4-bromophenyl) tetrahydropyran-3-carboxamide(1.10 g, 4.00 mmol) in acetonitrile (10 mL) and water (10 mL) was addedPhI(CF₃CO₂)₂ (1.90 g, 4.40 mmol) at rt. The reaction mixture was stirredat rt under nitrogen for 12 hrs. On completion, the reaction mixture wasdiluted with water (20 mL), extracted with ethyl acetate (3×50 mL),dried over anhydrous sodium sulfate and concentrated in vacuo to give ayellow oil. The yellow oil was purified by silica gel chromatography(dichloromethane:methanol=50:1) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ=7.47 (s, 4H), 3.90 (td, J=11.2, 4.0 Hz, 1H), 3.72 (d,J=11.2 Hz, 1H), 3.59-3.50 (m, 2H), 2.12-2.06 (m, 1H), 1.92 (ddt, J=14.2,10.2, 4.4 Hz, 1H), 1.76 (d, J=6.0 Hz, 1H), 1.61-1.52 (m, 1H).

Step 5—(±)-Ethyl 4-(3-aminotetrahydro-2H-pyran-3-yl) benzoate

To a mixture of (±)-3-(4-bromophenyl)tetrahydropyran-3-amine (200 mg,781 umol) and triethylamine (395 mg, 3.90 mmol) in ethanol (10.0 mL) wasadded Pd(dppf)Cl₂·CH₂Cl₂ (63.8 mg, 78.1 umol) in one portion undernitrogen. The mixture was flushed with monocarboxide (50 psi) threetimes, then it was heated to 85° C. and stirred for 16 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to give thecrude product. The crude product was purified by silica gelchromatography (dichloromethane:methanol=50:1) to give the titlecompound. LCMS: (ES⁺) m/z (M-NH₂)⁺=233.2, tR=0.569.

(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-2-bromobenzoate (IntermediateAG)

Step 1—Methyl 2-bromo-4-(bromomethyl)benzoate

To a solution of methyl 2-bromo-4-methylbenzoate (50.0 g, 218 mmol) inperchloromethane (500 mL) was added2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (3.58 g, 21.8 mmol)and 1-bromopyrrolidine-2,5-dione (42.7 g, 240 mmol). The mixture wasstirred at 70° C. for 12 hrs. On completion, the reaction mixture wascooled to rt and filtered. The filtrate was concentrated under reducedpressure to afford the title compound which was used into the next stepwithout further purification.

Step 2—Methyl 2-bromo-4-(cyanomethyl)benzoate

To a solution of trimethylsilanecarbonitrile (57.9 g, 584 mmol) andtetrabutylammonium fluoride (152 g, 584 mmol) in acetonitrile (900 mL)was added methyl 2-bromo-4-(bromomethyl)benzoate (60.0 g, 194 mmol). Themixture was stirred at rt for 10 min. On completion, to the reactionmixture was added water (500 mL), then the mixture was concentrated toremove most of the acetonitrile. The mixture was then extracted withethyl acetate (500 mL). The organic layer was separated, washed withbrine (100 mL), dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under vacuum to afford the crude product,which was purified by column chromatography (petroleum ether:ethylacetate=10:1 to 5:1) to afford the title compound. ¹H NMR (400 MHz,CDCl3) δ=7.76 (d, J=8.0 Hz, 1H), 7.60-7.56 (m, 1H), 7.29 (td, J=0.9, 8.0Hz, 1H), 3.87 (s, 3H), 3.71 (s, 2H).

Step 3—(±)-Methyl 2-bromo-4-(3-cyanotetrahydrofuran-3-yl)benzoate

To a solution of sodium hydride (3.46 g, 86.6 mmol) inN,N-dimethylformamide (100 mL) was added methyl2-bromo-4-(cyanomethyl)benzoate (10.0 g, 39.3 mmol) and1-chloro-2-(chloromethoxy)ethane (5.33 g, 41.3 mmol) at −10° C., andthen the mixture was stirred at 0° C. for 20 min. On completion, thereaction mixture was quenched by water at 0° C., and then extracted withethyl acetate (300 mL). The combined organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) toafford the title compound. ¹H NMR (300 MHz, CDCl₃) δ=7.82 (d, J=8.4 Hz,1H), 7.78 (d, J=2.0 Hz, 1H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 4.31 (d,J=9.2 Hz, 1H), 4.21-4.06 (m, 3H), 3.93 (s, 3H), 2.84-2.80 (m, 1H),2.46-2.41 (m, 1H).

Step 4—(±)-Methyl 2-bromo-4-(3-carbamoyltetrahydrofuran-3-yl)benzoate

To a solution of (±)-methyl2-bromo-4-(3-cyanotetrahydrofuran-3-yl)benzoate (11.0 g, 35.4 mmol) indimethyl sulfoxide (100 mL) was added hydrogen peroxide (20.1 g, 177mmol) and potassium carbonate (9.80 g, 70.9 mmol). The mixture wasstirred at rt for 2 hrs. On completion, the reaction mixture was dilutedwith water (200 ml) and then extracted with ethyl acetate (500 mL). Theorganic layer was dried over anhydrous sodium sulfate and filtered; thefiltrate was concentrated under vacuum to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ=7.76 (d, J=8.4 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H),7.42 (dd, J=8.4, 2.0 Hz, 2H), 7.20 (s, 1H), 4.44 (d, J=8.4 Hz, 1H), 3.86(s, 3H), 3.76-3.73 (m, 3H), 2.85-2.82 (m, 1H), 2.17-2.13 (m, 1H).

Step 5—(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-2-bromobenzoate

To a solution of (±)-methyl2-bromo-4-(3-carbamoyltetrahydrofuran-3-yl)benzoate (2.00 g, 6.09 mmol)in acetonitrile (5 mL) and water (1 mL) was added PhI(CF₃CO₂)₂ (2.62 g,6.09 mmol). The mixture was stirred at rt for 12 hrs. On completion, thereaction mixture was concentrated under vacuum to afford a residue. Theresidue was diluted with water (50 mL) and extracted with ethyl acetate(50 mL). The aqueous layer was separated and adjusted with NaHCO₃ (sat.)to pH=10, and then extracted with ethyl acetate (500 mL). The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under vacuum to afford the title compound. ¹H NMR (400MHz, DMSO-d₆) δ=7.90 (d, J=1.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59(dd, J=8.4, 1.6 Hz, 1H), 4.04-4.01 (m, 1H), 3.85 (s, 3H), 3.75 (d, J=8.4Hz, 1H), 3.69 (d, J=8.4 Hz, 1H), 2.23-2.16 (m, 2H), 2.06-1.99 (m, 1H).

(±)-Methyl 4-(3-amino-1-benzyl-pyrrolidin-3-yl)benzoate (IntermediateAH)

Step 1—(±)-1-Benzyl-3-(4-bromophenyl)pyrrolidin-3-ol

To a solution of 1-bromo-4-iodo-benzene (8.88 g, 31.3 mmol) intetrahydrofuran (80 mL) was added n-BuLi (2.5 M, 12.5 mL) at −78° C.,the mixture was stirred at −78° C. for 0.5 hr. Then1-benzylpyrrolidin-3-one (5.00 g, 4.67 mL) was added dropwise, and themixture was stirred at −78° C. for another 0.5 hrs, and then warmed tort with stirring for 12 hrs. On completion, the mixture was diluted withsaturated ammonium chloride (20 mL) and extracted with ethyl acetate(3×60 mL). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=5:1) to givethe title compound. ¹H NMR (400 MHz, CDCl3) δ=7.41-7.35 (m, 2H),7.32-7.28 (m, 2H), 7.27-7.22 (m, 3H), 7.21-7.15 (m, 2H), 3.65 (s, 2H),3.06 (dt, J=5.0, 8.8 Hz, 1H), 2.98 (br. s., 1H), 2.86 (d, J=9.4 Hz, 1H),2.51 (d, J=9.4 Hz, 1H), 2.49-2.42 (m, 1H), 2.28-2.19 (m, 1H), 2.16-2.07(m, 1H).

Step 2—(±)-N-[1-Benzyl-3-(4-bromophenyl)pyrrolidin-3-yl]acetamide

To a solution of (±)-1-benzyl-3-(4-bromophenyl)pyrrolidin-3-ol (6.10 g,18.36 mmol) in acetonitrile (75 mL) was added concentrated sulfuric acid(43.2 g, 440 mmol, 23.5 mL) at 0° C., and the reaction was stirred at rtfor 12 hrs. On completion, sodium hydroxide (18.7 g, 469 mmol) was addedto the mixture at 0° C., then water (30 mL) was added. The resultingmixture was extracted with ethyl acetate (3×50 mL), the combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=5:1 todichloromethane:methanol=10:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ=7.45-7.40 (m, 2H), 7.39-7.32 (m, 4H), 7.31-7.23 (m, 3H),6.17 (s, 1H), 3.79-3.60 (m, 2H), 3.00-2.91 (m, 2H), 2.91-2.84 (m, 1H),2.75 (dt, J=7.2, 8.1 Hz, 1H), 2.47-2.37 (m, 2H), 2.01 (s, 3H)

Step 3—(±)-1-Benzyl-3-(4-bromophenyl)pyrrolidin-3-amine

A solution of (±)-N-[1-benzyl-3-(4-bromophenyl)pyrrolidin-3-yl]acetamide(4.00 g, 10.7 mmol) in hydrochloric acid (6 M, 30 mL) was stirred at110° C. for 12 hrs. On completion, sodium hydroxide (34.3 g, 857 mmol)was added to the mixture at 0° C. and the mixture was filtered. Thefilter cake was dissolved in water (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic phase was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=7.40-7.35 (m, 2H), 7.33-7.22 (m,5H), 7.22-7.13 (m, 2H), 3.75-3.61 (m, 2H), 3.03 (dt, J=6.0, 8.7 Hz, 1H),2.81-2.74 (m, 1H), 2.73-2.65 (m, 1H), 2.63-2.50 (m, 1H), 2.24 (ddd,J=5.9, 9.3, 13.3 Hz, 1H), 1.98 (ddd, J=5.8, 7.7, 13.3 Hz, 1H).

Step 4—(±)-Methyl 4-(3-amino-1-benzyl-pyrrolidin-3-yl)benzoate

To a solution of (±)-1-benzyl-3-(4-bromophenyl)pyrrolidin-3-amine (2.50g, 7.55 mmol) in methanol (50 mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (616 mg,754 umol) and triethylamine (763 mg, 7.55 mmol). The mixture was purgedwith carbon monoxide (50 psi) three times, then, it was heated to 85° C.and stirred for 12 hrs. On completion, the reaction was filtered and thefiltrate was concentrated in vacuo. The mixture was acidified to pH=4-5with hydrochloric acid (1 N). The solution was washed with ethyl acetate(3×10 mL). The aqueous phase was basified to pH=8-9 with sodiumhydroxide, and extracted with dichloromethane (3×10 mL). The combinedorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title product (800 mg, 34% yield) asbrown oil. LCMS: (ES⁺) m/z (M+H)⁺=331.2, tR=0.497.

(±)-(3-Ethoxy-2-methyl-3-oxo-propanoyl)oxypotassium (Intermediate AD

A mixture of diethyl 2-methylpropanedioate (5.00 g, 28.7 mmol) and water(517 uL, 28.7 mmol) in ethanol (30 mL) was stirred at 40° C. for 2hours. Then a solution of potassium tert-butoxide (3.22 g, 28.7 mmol) inethanol (30 mL) was added dropwise during 0.5 hour and the reactionmixture was stirred at 40° C. for 2.5 hours. On completion, the reactionmixture was concentrated in vacuo and methyl tert-butyl ether (50 mL)was added. The mixture was filtered and the filter cake was washed witha solution of methyl tert-butyl ether and ethanol (30 mL:10 mL). Theresulting solid was dried in vacuo at 50° C. for 3 hours to give thetitle compound. ¹H NMR (400 MHz, D₂O) δ=4.10 (q, J=7.0 Hz, 2H), 3.28 (q,J=7.0 Hz, 1H), 1.22 (d, J=7.2 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).

(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-chloro-benzoate(Intermediate

Step 1—Methyl 3-chloro-4-methyl-benzoate

To a solution of 3-chloro-4-methyl-benzoic acid (20.0 g, 117 mmol) inmethanol (200 mL) was added thionyl chloride (65.6 g, 551 mmol). Themixture was heated to 100° C. and stirred at 100° C. for 16 hours. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified with silica gel chromatography (petroleumether:ethyl acetate=80:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=8.01 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),3.91 (s, 3H), 2.43 (s, 3H).

Step 2—Methyl 4-(bromomethyl)-3-chloro-benzoate

To a solution of methyl 3-chloro-4-methyl-benzoate (22.5 g, 121 mmol)and 2,2-azobisisobutyronitrile (2.00 g, 12.2 mmol) in carbontetrachloride (300 mL) was added 1-bromopyrrolidine-2,5-dione (23.8 g,134 mmol) portion wise. The mixture was heated to 100° C. and stirred at100° C. for 15 hours. On completion, the mixture was concentrated invacuo to give a solid. The solid was washed with water (200 mL) andextracted with DCM (2×150 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to give aresidue. The residue was purified with silica gel chromatograph(petroleum ether:ethyl acetate=100:1) to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ=7.99 (d, J=1.5 Hz, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H),7.45 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 3.86 (s, 3H).

Step 3—3-Chloro-4-(cyanomethyl)benzoate

To a solution of trimethylsilanecarbonitrile (8.47 g, 85.3 mmol) andtetrabutylammonium fluoride (1 M, 85.3 mL) in acetonitrile (600 mL) wasadded dropwise a solution of methyl 4-(bromomethyl)-3-chloro-benzoate(15.0 g, 56.9 mmol) in acetonitrile (120 mL), and the resulting mixturewas stirred at rt for 10 min. On completion, water (50 mL) was addedinto the mixture. The mixture was concentrated in vacuo. The residue wasextracted with dichloromethane (2×50 mL), the combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuumto give a residue. The residue was purified with silica gelchromatograph (petroleum ether:ethyl acetate=20:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=8.12 (d, J=1.8 Hz, 1H), 8.01 (dd,J=1.6, 8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 2H).

Step 4—(±)-Methyl 3-chloro-4-(3-cyanotetrahydrofuran-3-yl)benzoate

To a mixture of sodium hydride (419 mg, 10.5 mmol, 60% purity) in 10 mLN,N-dimethylformamide was added a solution of methyl3-chloro-4-(cyanomethyl)benzoate (1.00 g, 4.77 mmol) and1-chloro-2-(chloromethoxy)ethane (799 mg, 6.20 mmol) in 10 mLN,N-dimethylformamide dropwise at −10° C. to −5° C. Then the mixture wasstirred at 0° C. for 0.5 hour. The mixture was stirred at rt for 6hours. On completion, the reaction mixture was poured into ice-water (50mL) and stirred for 10 minutes. The reaction mixture was extracted withethyl acetate (3×50 mL). The organic layers were dried with anhydroussodium sulfate, filtrated and concentrated in vacuo. The residue waspurified by prep-column chromatography (petroleum ether:ethylacetate=20:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=8.16(d, J=1.5 Hz, 1H), 7.98 (dd, J=1.6, 8.2 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H),4.64 (d, J=9.0 Hz, 1H), 4.28-4.16 (m, 2H), 4.10 (dt, J=5.0, 8.4 Hz, 1H),3.97 (s, 3H), 2.94 (ddd, J=4.9, 7.3, 12.6 Hz, 1H), 2.66 (td, J=7.8, 12.8Hz, 1H).

Step 5—(±)-Methyl 4-(3-carbamoyltetrahydrofuran-3-yl)-3-chloro-benzoate

To a solution of (±)-methyl3-chloro-4-(3-cyanotetrahydrofuran-3-yl)benzoate (260 mg, 978 umol) andpotassium carbonate (54.1 mg, 391 umol) in dimethyl sulfoxide (6 mL) wasadded hydrogen peroxide (886 mg, 7.82 mmol). The mixture was stirred atrt for 3 hours. On completion, the mixture was washed with sat. sodiumthiosulfate (20 mL) and extracted with ethyl acetate (3×30 mL). Theorganic layers were dried with anhydrous sodium sulfate, filtrated andconcentrated to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=8.12(d, J=1.8 Hz, 1H), 7.99 (dd, J=1.6, 8.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H),5.49 (br. s., 2H), 4.52 (d, J=9.5 Hz, 1H), 4.19 (d, J=9.5 Hz, 1H), 4.11(d, J=6.5 Hz, 1H), 4.05-3.91 (m, 4H), 3.03-2.89 (m, 1H), 2.55-2.34 (m,1H).

Step 6—(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-chloro-benzoate

To a mixture of (±)-methyl4-(3-carbamoyltetrahydrofuran-3-yl)-3-chloro-benzoate (250 mg, 881 umol)in acetonitrile (3 mL) and water (3 mL) was added PhI(O2CCF3)2 (416 mg,969 umol) in one portion and the mixture was stirred at rt for 16 hours.On completion, the mixture was washed with 1 N hydrochloric acid (3 mL)and extracted with ethyl acetate (2×20 mL). Then the water layer waswashed with sat. sodium bicarbonate until pH=9.0. Then the mixture wasextracted with dichloromethane (3×30 mL). The organic layer was driedwith anhydrous sodium sulfate, filtrated and concentrated to give thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ=8.08 (d, J=1.5 Hz, 1H), 7.92(dd, J=1.6, 8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 4.27 (d, J=9.0 Hz, 1H),4.24-4.15 (m, 1H), 4.13-4.02 (m, 2H), 3.95 (s, 3H), 2.52 (td, J=8.8,12.3 Hz, 1H), 2.43-2.34 (m, 1H).

(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-bromo-benzoate(Intermediate AK)

Step 1—Methyl 3-bromo-4-(bromomethyl)benzoate

To a solution of methyl 3-bromo-4-methyl-benzoate (29.0 g, 126 mmol) and2,2-azobisisobutyronitrile (2.08 g, 12.6 mmol) in carbon tetrachloride(400 mL) was added N-bromosuccinimide (24.7 g, 139 mmol) portion-wise.The mixture was heated to 100° C. and stirred at 100° C. for 15 hrs. Oncompletion, the mixture was concentrated in vacuo to give a solid. Thesolid was washed with water (200 mL) and extracted with dichloromethane(2×200 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to give a residue. Theresidue was purified with silica gel chromatography (petroleumether:ethyl acetate=100:1) to afford the title compound. ¹H NMR (400MHz, CDCl3) δ=8.27 (d, J=1.6 Hz, 1H), 7.98 (dd, J=1.7, 8.0 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 4.63 (s, 2H), 3.95 (s, 3H).

Step 2—Methyl 3-bromo-4-(cyanomethyl)benzoate

To a solution of trimethylsilyl cyanide (13.5 g, 136 mmol, 17 mL) andtetrabutylammonium fluoride (1 M, 136 mL) in acetonitrile (600 mL) wasadded dropwise a solution of methyl 3-bromo-4-(bromomethyl)benzoate(28.0 g, 90.9 mmol) in acetonitrile (120 mL), and the resulting mixturewas stirred at rt for 10 min. On completion, the mixture was quenchedwith water (50 mL) and concentrated in vacuo. The leftover solution wasthen extracted with dichloromethane (2×200 mL), the combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuum to give a residue. The residue was purified with silica gelchromatography (petroleum ether:ethyl acetate=20:1) to afford the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=8.30 (d, J=1.6 Hz, 1H), 8.05 (dd,J=1.6, 8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 2H).

Step 3—(±)-Methyl 3-bromo-4-(3-cyanotetrahydrofuran-3-yl)benzoate

To a solution of sodium hydride (346 mg, 8.66 mmol) inN,N-dimethylformamide (30 mL) was added dropwise a solution of methyl3-bromo-4-(cyanomethyl)benzoate (1.00 g, 3.94 mmol) and1-chloro-2-(chloromethoxy)ethane (659 mg, 5.12 mmol) inN,N-dimethylformamide (10 mL) at −5° C. The resulting mixture wasstirred at 0° C. for 1 hr and then slowly warmed to rt and stirred at rtfor 1 hr. On completion, the mixture was slowly poured into ice water(100 mL), washed with brine and extracted with ethyl acetate (2×150 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to give a residue. The residuewas purified with silica gel chromatography (petroleum ether:ethylacetate=20:1) to afford the title compound. ¹H NMR (400 MHz, CDCl3)δ=8.37 (d, J=1.8 Hz, 1H), 8.02 (dd, J=1.8, 8.3 Hz, 1H), 7.48 (d, J=8.3Hz, 1H), 4.67 (d, J=9.2 Hz, 1H), 4.29 (d, J=9.2 Hz, 1H), 4.24-4.17 (m,1H), 4.10 (dt, J=5.0, 8.4 Hz, 1H), 3.97 (s, 3H), 2.98 (ddd, J=4.9, 7.4,12.7 Hz, 1H), 2.68 (td, J=7.7, 12.9 Hz, 1H).

Step 4—(±)-Methyl 3-bromo-4-(3-carbamoyltetrahydrofuran-3-yl)benzoate

To a solution of (±)-methyl3-bromo-4-(3-cyanotetrahydrofuran-3-yl)benzoate (1.00 g, 3.22 mmol) andpotassium carbonate (178 mg, 1.29 mmol) in dimethyl sulfoxide (10 mL)was added hydrogen peroxide (2.92 g, 25.7 mmol). The mixture was stirredat rt for 2 hrs. On completion, the mixture was quenched with sodiumsulfite solution (10 mL) and was extracted with ethyl acetate (3×40 mL).The combined organic layer was then washed with water (50 mL), brine (50mL), and was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=8.31 (d, J=1.8 Hz, 1H), 8.02 (dd, J=1.8, 8.2 Hz, 1H), 7.57 (d,J=8.2 Hz, 1H), 5.57-5.32 (m, 2H), 4.49 (d, J=9.3 Hz, 1H), 4.24 (d, J=9.3Hz, 1H), 4.14-4.04 (m, 1H), 3.95 (s, 3H), 3.94-3.88 (m, 1H), 3.01-2.98(m, 1H), 2.54-2.33 (m, 1H).

Step 5—(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-bromo-benzoate

To a mixture of (±)-methyl3-bromo-4-(3-carbamoyltetrahydrofuran-3-yl)benzoate (600 mg, 1.83 mmol)in acetonitrile (8 mL) and water (8 mL) was added PhI(O₂CCF₃)₂ (864 mg,2.01 mmol) in one portion, and the mixture was stirred at rt for 16 hrs.On completion, the mixture was concentrated in vacuo. 1N HCl (8 mL) wasadded into the mixture, and the mixture was washed with ethyl acetate(50 mL). The aqueous layer was then basified with sodium bicarbonate topH=9 and extracted with dichloromethane (2×50 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=8.29(d, J=1.8 Hz, 1H), 7.96 (dd, J=1.8, 8.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H),4.34 (d, J=8.8 Hz, 1H), 4.19 (dt, J=6.8, 8.5 Hz, 1H), 4.12 (d, J=8.8 Hz,1H), 4.05 (dt, J=3.5, 8.4 Hz, 1H), 3.95 (s, 3H), 2.58-2.48 (m, 1H),2.47-2.39 (m, 1H).

(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-cyano-benzoate(Intermediate AL)

To a mixture of (±)-methyl4-(3-aminotetrahydrofuran-3-yl)-3-bromo-benzoate (150 mg, 499 umol) andcopper cyanide (89.5 mg, 999 umol) in 1-methyl-2-pyrrolidinone (4 mL)was added copper iodide (19.0 mg, 99.9 umol) under a nitrogenatmosphere. The mixture was heated to 180° C. and stirred at 180° C. for5 hrs. On completion, the mixture was washed with water (30 mL) andextracted with dichloromethane (2×20 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuumto give a residue. The residue was purified with silica gelchromatography (dichloromethane:methanol=10:1) to afford the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=247.2, tR=0.703.

Methyl 4-(4-aminotetrahydropyran-4-yl)benzoate (Intermediate AM)

Step 1—2—(±)-Methyl-N-tetrahydropyran-4-ylidene-propane-2-sulfinamide

To a solution of tetrahydropyran-4-one (5.00 g, 49.9 mmol) and(±)-2-methylpropane-2-sulfinamide (5.39 g, 44.4 mmol) in tetrahydrofuran(80 mL) was added tetraethoxytitanium (20.0 g, 87.8 mmol) dropwise andthe reaction mixture was stirred at rt for 3 hrs. On completion, thereaction mixture was poured into 500 mL cooled water and the mixture wasfiltrated. The filtrate was extracted with dichloromethane (3×200 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtrated and concentrated in vacuo. The resulting oil was purified bysilica gel chromatography (petroleum ether:ethyl acetate=1:1) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=204.1, tR=0.695. ¹H NMR (400MHz, CDCl₃) δ=3.99 (t, J=6.0 Hz, 2H), 3.86 (t, J=5.8 Hz, 2H), 2.57 (t,J=5.8 Hz, 2H), 2.52 (t, J=6.2 Hz, 2H), 1.26 (s, 9H).

Step2—(±)-N-[4-(4-bromophenyl)tetrahydropyran-4-yl]-2-methyl-propane-2-sulfinamide

To a solution of 1-bromo-4-iodo-benzene (2.78 g, 9.84 mmol) in anhydroustetrahydrofuran (100 mL) was added n-butyllithium (2.5 M, 3.94 mL)dropwise at −70° C. and the reaction mixture was stirred under nitrogenfor 0.5 hr. Then a solution of(±)-2-methyl-N-tetrahydropyran-4-ylidene-propane-2-sulfinamide (2.00 g,9.84 mmol) in anhydrous tetrahydrofuran (20.0 mL) was added dropwise andthe reaction mixture was stirred at −70° C. for 0.5 hrs. Then thereaction mixture was warmed to rt during 1 hr and stirred at rt for 1hr. On completion, the reaction mixture was poured into 300 mL cooledwater. The aqueous phase was extracted with dichloromethane (3×100 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtrated and concentrated in vacuo. The resulting oil was purified bysilica gel chromatography (dichloromethane:methanol=10:1) to give thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ=7.50 (d, J=8.4 Hz, 2H), 7.33(d, J=8.4 Hz, 2H), 4.25-4.05 (m, 2H), 3.96-3.87 (m, 2H), 2.44-2.40 (m,2H), 2.21-2.11 (m, 2H), 1.16 (s, 9H).

Step 3—(±)-Methyl4-[4-(tert-butylsulfinylamino)tetrahydropyran-4-yl]benzoate

To a mixture of(±)-N-[4-(4-bromophenyl)tetrahydropyran-4-yl]-2-methyl-propane-2-sulfinamide(200 mg, 555 umol) and triethylamine (56.1 mg, 555 umol) in a mixture ofdimethyl sulfoxide (5 mL) and methanol (20 mL) was addedPd(dppf)Cl₂·CH₂Cl₂ (453 mg, 555 umol) and the reaction mixture wasstirred at 80° C. under carbon monoxide (50 psi) for 16 hrs. Oncompletion, the reaction mixture was concentrated in vacuo. Then 50 mLwater was added and the aqueous phase was extracted with dichloromethane(3×50 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtrated and concentrated in vacuo. The resulting oil waspurified by silica gel chromatography (dichloromethane:methanol=20:1) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=340.2, tR=0.666.

Step 4—Methyl 4-(4-aminotetrahydropyran-4-yl)benzoate

To a solution of (±)-methyl4-[4-(tert-butylsulfinylamino)tetrahydropyran-4-yl]benzoate (300 mg, 883umol) in a mixture of water (3 mL) and tetrahydrofuran (10 mL) was addediodine (44.8 mg, 176 umol) and the reaction mixture was stirred at 50°C. for 5 hrs. On completion, the reaction mixture was concentrated invacuo to remove the tetrahydrofuran. The aqueous phase was basified withaqueous saturated sodium bicarbonate until pH=9 and extracted withdichloromethane (3×20 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo to givethe title compound. LCMS: (ES⁺) m/z (M-NH2)⁺=219.1, tR=0.989.

(±)-Ethyl 4-(3-aminotetrahydrofuran-3-yl)benzoate (Intermediate AN)

Step 1—1-Chloro-2-(chloromethoxy)ethane

To a solution of paraformaldehyde (29.5 g, 328 mmol) in dichloromethane(600 mL) was bubbled HCl (gas) at −10° C. until the solution becameclear. Then, 2-chloroethanol (80.0 g, 994 mmol, 66.7 mL) was addeddropwise, and the HCl gas was discontinued. The reaction mixture wasstirred at −10° C. for 10 mins. On completion, the reaction was pouredinto a suspension of anhydrous potassium carbonate (200 g) indichloromethane (300 mL) and stirred until bubbling ceased. The reactionmixture was filtered and concentrated in vacuo to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=5.54 (s, 2H), 3.96 (t, J=5.6 Hz,2H), 3.70 (t, J=5.6 Hz, 2H).

Step 2—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-carbonitrile

To a solution of NaH (4.69 g, 117 mmol, 60% purity) inN,N-dimethylformamide (200 mL) was added 2-(4-bromophenyl)acetonitrile(10.0 g, 51.0 mmol, CAS #16532-79-9) and1-chloro-2-(chloromethoxy)ethane (7.90 g, 61.2 mmol) inN,N-dimethylformamide (100 mL) portion-wise at 0° C. under a nitrogen.The reaction mixture was warmed to rt with stirring for 12 hrs. Oncompletion, to the reaction mixture was added water (200 mL) then it wasextracted with ethyl acetate (3×500 mL). The organic layers were washedwith brine (200 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to give a black solid. The solid was purified bysilica gel chromatography (petroleum ether:ethyl acetate=50:1) to givethe title compound. ¹H NMR (400 MHz, CDCl3) δ=7.47 (d, J=8.5 Hz, 2H),7.29 (d, J=8.8 Hz, 2H), 4.26 (d, J=9.0 Hz, 1H), 4.14-4.04 (m, 2H), 3.96(d, J=9.0 Hz, 1H), 2.78-2.68 (m, 1H), 2.34 (td, J=8.1, 13.0 Hz, 1H).

Step 3—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-carboxamide

To a mixture of (±) 3-(4-bromophenyl)tetrahydrofuran-3-carbonitrile(8.00 g, 31.7 mmol) and H₂O₂ (13.7 g, 121 mmol, 11.6 mL, 30% purity) indimethyl sulfoxide (60 mL) was added potassium carbonate (1.75 g, 12.7mmol) in one portion at rt. Then the mixture was heated to 60° C.(oil-bath temperature) and stirred for 3 hours. On completion, thereaction mixture was diluted with water (120 mL), filtered and dried invacuo to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.54 (d,J=8.5 Hz, 2H), 7.30 (br. s., 1H), 7.27 (d, J=8.5 Hz, 2H), 7.08 (br. s.,1H), 4.45 (d, J=8.5 Hz, 1H), 3.82-3.69 (m, 3H), 2.82 (ddd, J=5.3, 7.2,12.4 Hz, 1H), 2.10 (td, J=8.0, 12.5 Hz, 1H).

Step 4—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-amine

To a solution of (±) 3-(4-bromophenyl)tetrahydrofuran-3-carboxamide(8.33 g, 30.8 mmol) in acetonitrile (40 mL) and water (40 mL) was addedPhI(OAc)₂ (11.92 g, 37.01 mmol) at rt. The reaction mixture was stirredat rt for 12 hrs. On completion, the reaction mixture was concentratedin vacuo. The residue was acidified with HCl (2N, 15 mL) to pH=2 and theaqueous layer was washed with ethyl acetate (100 mL). To the aqueouslayer was then added saturated NaHCO₃ to pH=9. The aqueous layer wasthen extracted with ethyl acetate (3×200 mL). The combined organic layerwas washed with brine (100 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=7.50 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 4.24-4.14 (m,1H), 4.14-4.04 (m, 1H), 3.95-3.83 (m, 2H), 2.37 (td, J=8.8, 12.5 Hz,1H), 2.14 (ddd, J=4.1, 7.5, 12.2 Hz, 1H)

Step 5—(±)-Ethyl 4-(3-aminotetrahydrofuran-3-yl)benzoate

To a mixture of (±) 3-(4-bromophenyl)tetrahydrofuran-3-amine (4.93 g,20.4 mmol) and TEA (10.3 g, 14.0 mL) in ethanol (50 mL) was addedPd(dppf)Cl₂-DCM (1.66 g, 2.04 mmol) in one portion under nitrogen. Themixture was flushed with CO (50 psi) three times then heated to 85° C.and stirred for 16 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give a residue. The residue wasdissolved in a mixture of dichloromethane and water (40 mL/80 mL). Then,the mixture was acidified with HCl (2 N) 60 mL to pH=2, and washed withDCM. The aqueous layer was basified with saturated NaHCO₃ (80 mL). Thenthe mixture was extracted with dichloromethane (3×50 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M-NH₂)⁺=219.2, tR=0.570.

(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-fluorobenzoate(Intermediate AO)

Step 1—Methyl 3-fluoro-4-methylbenzoate

A solution of 3-fluoro-4-methyl-benzoic acid (10.0 g, 64.9 mmol) inmethanol (150 mL) was heated from rt to 65° C. Then thionyl chloride(12.3 g, 103 mmol, 7.50 mL) was added dropwise at 65° C., and themixture was stirred at 65° C. for 16 hours. On completion, the mixturewas concentrated, diluted with ethyl acetate (150 mL), washed with water(2×50 mL) and brine (1×50 mL), dried and concentrated to get the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=7.64 (d, J=8.0 Hz, 1H), 7.58 (d,J=10.3 Hz, 1H), 7.22-7.12 (m, 1H), 3.83 (s, 3H), 2.25 (d, J=1.3 Hz, 3H).

Step 2—Methyl 4-(bromomethyl)-3-fluorobenzoate

To a solution of methyl 3-fluoro-4-methyl-benzoate (9.90 g, 58.9 mmol)in carbon tetrachloride (120 mL) was added 2,2-azobisisobutyronitrile(966 mg, 5.89 mmol) and n-bromosuccinimide (11.0 g, 61.8 mmol) at rt,then the mixture was heated to reflux at 78° C. for 16 hours. Oncompletion, the solvent was removed in vacuo, and the residue wasdissolved with ethyl acetate (200 mL), washed with water (2×50 mL),brine (1×50 mL), dried and concentrated to give the title compound(crude). ¹H NMR (400 MHz, CDCl₃) δ=7.83 (dd, J=1.1, 7.9 Hz, 1H), 7.74(dd, J=1.1, 9.9 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 4.53 (s, 2H), 3.94 (s,3H).

Step 3—Methyl 4-(cyanomethyl)-3-fluorobenzoate

To a solution of trimethylsilanecarbonitrile (400 mg, 4.04 mmol) andtetrabutylammonium fluoride (1.06 g, 4.04 mmol) in acetonitrile (20.0mL) was added a solution of methyl 4-(bromomethyl)-3-fluoro-benzoate(500 mg, 2.02 mmol) in acetonitrile (10 mL) dropwise at 0° C. Themixture was stirred at rt for 10 minutes. On completion, water (50 mL)was added into the mixture. Then the mixture was extracted with ethylacetate (2×50 mL), the combined organic phase was dried over withanhydrous sodium sulfate, filtered, and concentrated in vacuo to givebrown oil. The oil was purified by silica gel chromatograph (petroleumether:ethyl acetate=20:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=7.89 (d, J=7.8 Hz, 1H), 7.78 (d, J=10.3 Hz, 1H), 7.56 (t, J=7.7Hz, 1H), 3.95 (s, 3H), 3.84 (s, 2H).

Step 4—(±)-Methyl 4-(3-cyanotetrahydrofuran-3-yl)-3-fluorobenzoate

A solution of sodium hydride (372 mg, 15.5 mmol) in dimethyl formamide(10 mL) was stirred at −5° C., then a solution of methyl4-(cyanomethyl)-3-fluoro-benzoate (1.00 g, 5.18 mmol) and1-chloro-2-(chloromethoxy)ethane (734 mg, 5.70 mmol) in dimethylformamide (10 mL) was added dropwise at −5° C. The mixture was stirredat rt for 16 hours. On completion, the mixture was poured into water (60mL), then the aqueous phase was extracted with ethyl acetate (3×30 mL).The combined extracts were washed with brine (30 mL), dried andconcentrated. The mixture was purified by column chromatography(petroleum ether:ethyl acetate=20:1 to 5:1) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ=7.88 (dd, J=1.4, 8.2 Hz, 1H), 7.84-7.77 (m,1H), 7.59-7.51 (m, 1H), 4.52 (dd, J=2.0, 9.0 Hz, 1H), 4.28-4.19 (m, 1H),4.13 (d, J=7.0 Hz, 2H), 3.98 (s, 3H), 2.89-2.79 (m, 1H), 2.60 (td,J=7.8, 12.9 Hz, 1H).

Step 5—(±)-Methyl 4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluorobenzoate

To a suspension of (±)-methyl4-(3-cyanotetrahydrofuran-3-yl)-3-fluoro-benzoate (610 mg, 2.45 mmol)and potassium carbonate (135 mg, 980 umol) in dimethyl sulfoxide (20 mL)was added hydrogen peroxide (30% wt, 833 mg, 7.35 mmol, 750 uL) in oneportion at rt. Then the mixture was stirred at rt for 3 hours. Oncompletion, the mixture was poured into water (60 mL), then the aqueousphase was extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed with brine (30 mL), dried and concentrated to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=268.0, tR=0.981.

Step 6—(±)-Methyl 4-(3-aminotetrahydrofuran-3-yl)-3-fluorobenzoate

To a solution of methyl4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluoro-benzoate (390 mg, 1.46mmol) in acetonitrile (25 mL) and water (25 mL) was added PhI(CO₂CF₃)₂(787 mg, 1.83 mmol) in one portion at rt, then the mixture was stirredat rt for 16 hours. On completion, the acetonitrile was removed invacuo, and the residue was diluted with water (60 mL) and acidified with1N HCl, then extracted with dichloromethane (2×30 mL) and the organicphase was discarded. Then the aqueous phase was basified with 1 M sodiumhydroxide to pH=7-8, and the mixture was extracted with ethyl acetate(3×30 mL). The combined extracts were washed with brine (30 mL), driedand concentrated to give the title compound. LCMS: (ES⁺) m/z(M-NH2)⁺=223.0, tR=1.01.

2-(Chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(Intermediate AP)

Step 1—1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde

To a mixture of sodium hydride (500 mg, 12.5 mmol) inN,N-dimethylformamide (10 mL) was added 1H-imidazole-2-carbaldehyde(1.00 g, 10.4 mmol). The reaction mixture was stirred at rt for 1.5 hrs.Then 2-(chloromethoxy)ethyl-trimethyl-silane (2.08 g, 12.5 mmol) wasadded at 0° C. The reaction mixture was stirred at rt for 16 hrs. Oncompletion, the mixture was quenched by water (50 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified bychromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=9.85 (s, 1H), 7.39 (s, 1H), 7.35 (s,1H), 5.80 (s, 2H), 3.59 (t, J=8.4 Hz, 2H), 0.92-1.00 (m, 2H), 0.003 (s,9H).

Step 2—1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde

To a solution of1-(2-trimethylsilylethoxymethyl)imidazole-2-carbaldehyde (2.00 g, 8.84mmol) in methanol (20 mL) was added sodium hydroboronate (334 mg, 8.84mmol) in three portions at −10° C. Then the reaction mixture was stirredat rt for 1 h. On completion, the mixture was quenched with water (20mL) and extracted with dichloromethane (3×30 mL). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=10:1 to 1:1) to give the title compound. ¹H NMR (400 MHz,DMSO-d6) δ=7.26 (s, 1H), 6.86 (d, J=1.2 Hz, 1H), 5.41 (s, 2H), 5.36 (t,J=4.8 Hz, 1H), 4.54 (d, J=5.2 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H), 0.86-0.90(m, 2H), 0.00 (s, 9H).

Step3—2-(Chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a mixture of [1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methanol(300 mg, 1.31 mmol) and triethylamine (265 mg, 2.62 mmol) indichloromethane (10 mL) was added methanesulfonyl chloride (130 mg, 1.13mmol) in one portion at 0° C. under nitrogen. The mixture was stirred at0° C. for 1 h. On completion, the mixture was quenched with saturatedaqueous citric acid solution (10 mL) and water (30 mL), then extractedwith dichloromethane (2×30 mL). The combined organic layers were washedwith saturated aqueous sodium bicarbonate (60 mL), dried over sodiumsulfate, and concentrated in vacuo to give the title compound, which wasused in next step directly. ¹H NMR (400 MHz, CDCl3) δ=7.13-7.18 (m, 2H),5.46 (s, 2H), 4.92 (s, 2H), 3.54-3.58 (m, 2H), 0.94 (t, J=8.4 Hz, 2H),0.00 (s, 9H).

(±)-4-(Chloromethyl)-1-methyl-pyrrolidin-2-one (Intermediate AQ)

Step 1—(±)-Methyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate

To a solution of dimethyl 2-methylenebutanedioate (15.0 g, 94.8 mmol) inmethanol (150 mL) was added methanamine (4.42 g, 142 mmol), and themixture was stirred at rt for 12 hrs. On completion, the reaction wasconcentrated in vacuo and the residue was purified by chromatography onsilica gel (petroleum ether:ethyl acetate=5:1 todichloromethane:methanol=10:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ=3.74 (s, 3H), 3.65-3.50 (m, 2H), 3.30-3.14 (m, 1H), 2.85(s, 3H), 2.74-2.55 (m, 2H)

Step 2—(±)-4-(Hydroxymethyl)-1-methyl-pyrrolidin-2-one

To a solution of (±)-methyl 1-methyl-5-oxo-pyrrolidine-3-carboxylate(4.00 g, 25.4 mmol) in methanol (10 mL) was added sodium borohydride(2.89 g, 76.3 mmol) at 0° C., and the mixture was stirred at rt for 3hrs. On completion, the reaction was adjusted pH to 4-5 withconcentrated hydrochloric acid and the mixture was concentrated invacuo. The residue was diluted with solvent (50 mL,dichloromethane:methanol=10:1), filtered, and the filtrate wasconcentrated to give the title compound. ¹H NMR (400 MHz, CDCl3)δ=3.72-3.60 (m, 2H), 3.58-3.46 (m, 1H), 3.35-3.25 (m, 1H), 2.88 (s, 3H),2.66-2.50 (m, 2H), 2.31 (m, 1H)

Step 3—(±)-4-(Chloromethyl)-1-methyl-pyrrolidin-2-one

To a solution of (±)-4-(hydroxymethyl)-1-methyl-pyrrolidin-2-one (1.00g, 7.74 mmol) in dichloromethane (8 mL) was added thionyl chloride (2.30g, 19.3 mmol), and the mixture was stirred at 60° C. for 5 hrs. Oncompletion, the mixture was concentrated in vacuo and the residue waspurified by chromatography on silica gel (petroleum ether:ethylacetate=1:1 to dichloromethane:methanol=20:1) to give the titlecompound. Used crude in the next reaction.

3-(Chloromethyl)tetrahydrofuran (Intermediate AR)

Step 1—Tetrahydrofuran-3-ylmethanol

To a solution of tetrahydrofuran-3-carbaldehyde (3.00 g, 29.9 mmol) inanhydrous methanol (30 mL) was added sodium borohydride (1.70 g, 44.9mmol) in 3 portions. The mixture was stirred at 0° C. for 2 hrs. Oncompletion, the reaction was quenched with ice water (5 mL) andconcentrated in vacuo. The residue was triturated with a mixture ofdichloromethane:methanol=10:1 (30 mL). The mixture was filtered; thefiltrate was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound. ¹H NMR (300 MHz,CDCl3) δ=3.84-3.74 (m, 2H), 3.73-3.62 (m, 1H), 3.61-3.41 (m, 3H), 3.18(br. s., 1H), 2.51-2.33 (m, 1H), 2.03-1.89 (m, 1H), 1.57 (dt, J=7.3,12.9 Hz, 1H).

Step 2—3-(Chloromethyl)tetrahydrofuran

To a solution of tetrahydrofuran-3-ylmethanol (150 mg, 1.47 mmol) andtriethylamine (371 mg, 3.68 mmol) in anhydrous dichloromethane (10 mL)was added methanesulfonyl chloride (252 mg, 2.21 mmol) dropwise at 0° C.Then the mixture was stirred at rt for 2 hrs. On completion, thereaction mixture was filtered through a plug of Celite and the filtratewas concentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=3.84-3.75 (m, 2H), 3.69 (q, J=7.8 Hz, 1H), 3.59-3.52 (m, 1H),3.48-3.42 (m, 1H), 2.67-2.48 (m, 1H), 2.14-1.95 (m, 1H), 1.70-1.52 (m,1H).

3-(Chloromethyl)oxetane (Intermediate AS)

To a solution of oxetan-3-ylmethanol (500 mg, 5.68 mmol) andtriethylamine (1.44 g, 14.2 mmol) in anhydrous dichloromethane (20 mL)was added methanesulfonyl chloride (975 mg, 8.52 mmol) dropwise at 0° C.Then, the mixture was stirred at rt for 2 hrs. On completion, thereaction mixture was quenched with ice water (10 mL), diluted with water(20 mL) and extracted with dichloromethane (2×20 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=4.78-4.71 (m, 2H), 4.44-4.37 (m, 2H), 3.61 (s, 2H), 3.39-3.28(m, 1H).

(±)-Ethyl 6-(3-aminotetrahydrofuran-3-yl)pyridine-3-carboxylate(Intermediate AT)

Step 1—5-bromo-2-(bromomethyl)pyridine

To a solution of 5-bromo-2-methyl-pyridine (32.0 g, 186 mmol) in carbontetrachloride (50 mL) was added 2,2-azobisisobutyronitrile (2.44 g, 14.8mmol) and N-bromosuccinimide (39.7 g, 223 mmol), and the mixture wasstirred at 90° C. for 12 hrs under nitrogen atmosphere. On completion,the mixture was concentrated to give a residue. The residue was purifiedby chromatography on silica gel (petroleum ether:ethyl acetate=80:1 to20:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=8.62 (d,J=2.4 Hz, 1H), 7.62 (dd, J=2.4, 8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H),4.41 (s, 2H).

Step 2—2-(5-bromo-2-pyridyl)acetonitrile

To a solution of trimethylsilyl cyanide (5.34 g, 53.8 mmol) inacetonitrile (50 mL) was added tetrabutylammonium fluoride (1 M intetrahydrofuran, 35.8 mL, 35.8 mmol), and the mixture was stirred at rtfor 0.1 hr. Then 5-bromo-2-(bromomethyl)pyridine (9.00 g, 35.8 mmol) inacetonitrile (20 mL) was added and the mixture was stirred at rt for 0.2hr. On completion, the reaction mixture was concentrated to remove theacetonitrile and then the mixture was diluted with water (30 mL) andextracted with ethyl acetate (3×80 mL). The combined organic layer waswashed with brine (3×30 mL), dried over anhydrous sodium sulfate,filtered and concentrated to give a residue. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=50:1 to 5:1)to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=8.71 (d, J=2.3Hz, 1H), 8.10 (dd, J=2.3, 8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 4.22 (s,2H).

Step 3—(±)-3-(5-bromo-2-pyridyl)tetrahydrofuran-3-carbonitrile

To a mixture of sodium hydride (1.70 g, 42.44 mmol, 60% purity) indimethyl formamide (200 mL) was added 2-(5-bromo-2-pyridyl)acetonitrile(3.80 g, 19.2 mmol) and 1-chloro-2-(chloromethoxy)ethane (2.61 g, 20.2mmol) in dimethyl formamide (150 mL) at −10° C. The mixture was stirredat −10° C. for 0.3 hr. On completion, the reaction mixture was quenchedby addition of water (50 mL) at 0° C., and then extracted with ethylacetate (3×200 mL). The combined organic layers were washed with brine(7×200 mL), dried over anhydrous sodium, filtered and concentrated underreduced pressure to give a residue. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=10:1 to 5:1)to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=8.60 (d, J=1.9 Hz,1H), 7.81 (dd, J=2.3, 8.3 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.31 (d,J=8.8 Hz, 1H), 4.14-4.06 (m, 3H), 2.75-2.66 (m, 1H), 2.65-2.57 (m, 1H).

Step 4—(±)-ethyl 6-(3-cyanotetrahydrofuran-3-yl)pyridine-3-carboxylate

To a solution of (±)-3-(5-bromo-2-pyridyl)tetrahydrofuran-3-carbonitrile(2.40 g, 9.48 mmol) in ethanol (50 mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (774mg, 948 umol) and triethylamine (2.88 g, 28.44 mmol). The mixture waspurged with CO (50 psi) three times, then it was heated to 90° C. andstirred for 12 hrs under CO (50 psi). On completion, the reaction wasconcentrated in vacuo to give a residue. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=50:1 to 3:1)to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=9.22 (d, J=2.1 Hz,1H), 8.37 (dd, J=2.2, 8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 4.50-4.40 (m,3H), 4.28-4.18 (m, 3H), 2.89-2.81 (m, 1H), 2.78-2.68 (m, 1H), 1.44 (t,J=7.1 Hz, 3H).

Step 5—(±)-ethyl6-(3-carbamoyltetrahydrofuran-3-yl)pyridine-3-carboxylate

To a solution of (±)-ethyl6-(3-cyanotetrahydrofuran-3-yl)pyridine-3-carboxylate (700 mg, 2.84mmol) in dimethyl sulfoxide (6 mL) was added potassium carbonate (785mg, 5.68 mmol) and hydrogen peroxide (3.22 g, 28.4 mmol, 30% purity),and the mixture was stirred at rt for 12 hrs. On completion, the mixturewas diluted with water (10 mL) and extracted with dichloromethane (3×20mL). The organic layer was washed with water (3×10 mL), dried overanhydrous sodium sulfate, filtered and concentrated to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=9.19 (dd, J=0.8, 2.2 Hz, 1H), 8.31(dd, J=2.3, 8.3 Hz, 1H), 7.46 (dd, J=0.8, 8.2 Hz, 1H), 6.59 (br. s.,1H), 5.45 (br. s., 1H), 4.57 (d, J=9.2 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H),4.27 (d, J=9.2 Hz, 1H), 4.13-4.05 (m, 1H), 3.97 (dt, J=5.3, 8.4 Hz, 1H),2.95 (ddd, J=5.5, 7.6, 12.7 Hz, 1H), 2.56 (ddd, J=6.9, 8.3, 12.5 Hz,1H), 1.43 (t, J=7.2 Hz, 3H).

Step 6—(±)-Ethyl 6-(3-aminotetrahydrofuran-3-yl)pyridine-3-carboxylate

To a solution of (±)-ethyl6-(3-carbamoyltetrahydrofuran-3-yl)pyridine-3-carboxylate (200 mg, 756umol) in acetonitrile (5 mL) and water (1 mL) was added[bis(trifluoroacetoxy)iodo]benzene (390 mg, 908 umol). The mixture wasstirred at 30° C. for 12 hrs. On completion, the mixture wasconcentrated to remove acetonitrile, diluted with saturated potassiumcarbonate (10 mL) and extracted with dichloromethane (3×50 mL). Thecombined organic layer was washed with water (3×30 mL), dried overanhydrous sodium sulfate, filtered and concentrated to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=9.16 (d, J=1.5 Hz, 1H), 8.28 (d, 8.2Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 4.45-4.39 (m, 2H), 4.21 (q, J=7.9 Hz,1H), 4.16-4.06 (m, 3H), 2.65-2.49 (m, 2H), 1.40 (t, J=7.6 Hz, 3H).

(±)-Ethyl 5-(3-aminotetrahydrofuran-3-yl)pyridine-2-carboxylate(Intermediate AU)

Step 1—2-bromo-5-(bromomethyl)pyridine

To a solution of 2-bromo-5-methyl-pyridine (20.0 g, 116 mmol) inacetonitrile (300 mL) was added 2,2-azobisisobutyronitrile (1.91 g,11.63 mmol) and N-bromosuccinimide (24.8 g, 139 mmol), and the mixturewas stirred at 90° C. for 12 hrs under nitrogen atmosphere. Oncompletion, the reaction was concentrated to give a residue. The residuewas purified by chromatography on silica gel (petroleum ether:ethylacetate=10:1 to 5:1) to give the title compound. ¹H NMR (400 MHz, CDCl3)δ=8.40 (d, J=2.4 Hz, 1H), 7.62 (dd, J=2.6, 8.2 Hz, 1H), 7.51 (d, J=8.3Hz, 1H), 4.42 (s, 2H).

Step 2—2-(6-bromo-3-pyridyl)acetonitrile

To a solution of trimethylsilyl cyanide (2.37 g, 23.9 mmol) inacetonitrile (30 mL) was added tetrabutylammonium fluoride (1 M intetrahydrofuran, 6.25 g, 23.9 mmol), and the mixture was stirred at rtfor 0.1 hr. Then 2-bromo-5-(bromomethyl)pyridine (4.00 g, 15.9 mmol) inacetonitrile (20 mL) was added, and the mixture was stirred at rt for0.2 hr. On completion, the reaction was concentrated to removeacetonitrile and then diluted with water (30 mL). The mixture wasextracted with ethyl acetate (3×80 mL), washed with brine (3×30 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give a residue. The residue was purified by chromatography on silicagel (petroleum ether:ethyl acetate=50:1 to 5:1) to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=8.34 (d, J=1.8 Hz, 1H), 7.61-7.56(m, 1H), 7.55-7.51 (m, 1H), 3.74 (s, 2H).

Step 3—(±)-3-(6-bromo-3-pyridyl)tetrahydrofuran-3-carbonitrile

To a mixture of sodium hydride (8.93 g, 22.3 mmol, 60% purity) indimethyl formamide (200 mL) was added(±)-2-(6-bromo-3-pyridyl)acetonitrile (2.00 g, 10.1 mmol) and1-chloro-2-(chloromethoxy)ethane (1.37 g, 10.6 mmol) in dimethylformamide (50 mL) at −10° C., and the mixture was stirred at −10° C. for0.3 hr. On completion, the reaction mixture was quenched by addition ofwater (50 mL) at 0° C., and then extracted with ethyl acetate (3×200mL). The combined organic layers were washed with brine (7×200 mL),dried over anhydrous sodium, filtered and concentrated under reducedpressure to give a residue. The residue was purified by chromatographyon silica gel (petroleum ether:ethyl acetate=10:1 to 5:1) to give thetitle compound. ¹H NMR (400 MHz, CDCl3) δ=8.53 (d, J=2.5 Hz, 1H), 7.67(dd, J=2.5, 8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 4.32 (d, J=9.0 Hz, 1H),4.24-4.13 (m, 2H), 4.07 (d, J=9.0 Hz, 1H), 2.87-2.83 (m, 1H), 2.48-2.35(m, 1H).

Step 4—(±)-ethyl 5-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxylate

To a solution of (±)-3-(6-bromo-3-pyridyl)tetrahydrofuran-3-carbonitrile(1.50 g, 5.93 mmol) in ethanol (50 mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (484mg, 593 umol) and triethylamine (1.80 g, 17.8 mmol). The mixture waspurged with carbon monoxide (50 psi) three times, then it was heated to90° C. and stirred for 12 hrs under carbon monoxide (50 psi). Oncompletion, the reaction was concentrated to give a residue. The residuewas purified by chromatography on silica gel (petroleum ether:ethylacetate=50:1 to 2:1) to give the title compound. ¹H NMR (400 MHz, CDCl3)δ=8.89 (d, J=2.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.98 (dd, J=2.3, 8.3Hz, 1H), 4.50 (q, J=7.2 Hz, 2H), 4.36 (d, J=9.3 Hz, 1H), 4.27-4.12 (m,3H), 2.94-2.83 (m, 1H), 2.50-2.45 (m, 1H), 1.45 (t, J=7.2 Hz, 3H).

Step 5—(±)-ethyl5-(3-carbamoyltetrahydrofuran-3-yl)pyridine-2-carboxylate

To a solution of (±)-ethyl5-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxylate (500 mg, 2.03mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (561mg, 4.06 mmol) and hydrogen peroxide (1.15 g, 10.1 mmol, 30% in water),and the mixture was stirred at rt for 12 hrs. On completion, the mixturewas diluted with water (10 mL) and extracted with dichloromethane (3×20mL). The organic layer was washed with water (3×10 mL), dried overanhydrous sodium sulfate, filtered and concentrated to give the titlecompound. ¹H NMR (400 MHz, CDCl3) δ=8.71 (s, 1H), 8.15 (d, J=8.2 Hz,1H), 7.81 (dd, J=2.0, 8.2 Hz, 1H), 5.98-5.52 (m, 2H), 4.56-4.45 (m, 3H),4.18-4.10 (m, 1H), 4.08-3.98 (m, 2H), 2.92 (ddd, J=5.8, 7.6, 12.9 Hz,1H), 2.45-2.33 (m, 1H), 1.46 (t, J=7.1 Hz, 3H)

Step 6—(±)-ethyl 5-(3-aminotetrahydrofuran-3-yl)pyridine-2-carboxylate

To a solution of (±)-ethyl5-(3-carbamoyltetrahydrofuran-3-yl)pyridine-2-carboxylate (300 mg, 1.14mmol) in acetonitrile (5 mL) and water (1 mL) was added[bis(trifluoroacetoxy)iodo]benzene (585 mg, 1.36 mmol). The mixture wasstirred at rt for 12 hrs. On completion, the mixture was concentrated toremove acetonitrile and diluted with saturated potassium carbonate water(10 mL) and extracted with dichloromethane (3×50 mL). The organic layerwas washed with water (3×30 mL), dried over anhydrous sodium sulfate,filtered and concentrated to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=8.92 (s., 1H), 8.15-8.05 (m, 1H), 8.02-7.95 (m, 1H), 4.50 (q,J=7.0 Hz, 2H), 4.28-4.07 (m, 2H), 3.96-3.84 (m., 2H), 2.45-2.39 (m, 1H),2.26-2.15 (m., 1H), 1.47 (t, J=7.1 Hz, 3H).

(±)-Ethyl 2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)acetate (IntermediateAV) & (±)-Ethyl2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)-2-methylpropanoate(Intermediate AW)

Step 1—(±)-3-(4-Bromophenyl)tetrahydrofuran-3-carbonitrile

To a solution of sodium hydride (4.69 g, 117 mmol, 60% oil dispersion)in N,N-dimethyl formamide (200 mL) was added2-(4-bromophenyl)acetonitrile (10.0 g, 51.01 mmol) and1-chloro-2-(chloromethoxy)ethane (7.90 g, 61.2 mmol) in N,N-dimethylformamide (100 mL) dropwise at 0° C. under nitrogen. The reactionmixture was warmed to rt with stirring for 12 hrs. On completion, thereaction mixture was poured into water (1200 mL) and extracted withethyl acetate (3×500 mL). The combined organic layers were washed withbrine (200 mL), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=50:1 to 20:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=252.0, tR=1.228

Step 2—(±)-Ethyl 2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)acetate

A solution of (±)-3-(4-bromophenyl)tetrahydrofuran-3-carbonitrile (1.41g, 5.59 mmol), allyl(chloro)palladium (51.16 mg, 279.50 umol),dimethylaminopyridine (68.3 mg, 559 umol), 1.1′-alnaphthalene-2.2-diphenyl phosphine (348.25 mg, 559.00 umol) in xylene(20 mL) was stirred at rt for 30 min under nitrogen. Then(3-ethoxy-3-oxo-propanoyl)oxypotassium (1.90 g, 11.18 mmol) was added inone portion and the reaction mixture was stirred at 140° C. for 16 hrs.On completion, ethyl acetate (20 mL) was added to the mixture, thesolution was then washed with water (2×10 mL) and brine (10 mL). Theorganic layer was separated, dried and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=20:1 to 10:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=7.37 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 4.29 (d, J=9.0Hz, 1H), 4.17-4.07 (m, 4H), 3.96 (d, J=8.8 Hz, 1H), 3.55 (s, 2H), 2.71(td, J=6.1, 12.6 Hz, 1H), 2.38 (td, J=8.1, 13.0 Hz, 1H), 1.19 (t, J=7.2Hz, 3H).

Step 3—(±)-Ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (1.02 g, 3.93 mmol) inN,N-dimethyl formamide (10 mL) was added sodium hydride (377 mg, 15.7mmol) in one portion at 0° C. Then iodomethane (3.35 g, 23.6 mmol) wasadded to the solution dropwise and the mixture was stirred at 60° C. for4 hrs. On completion, the mixture was poured into water (50 mL) and themixture was extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with water (20 mL), brine (20 mL), dried overanhydrous sodium sulfate, and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=20:1 to 10:1) to give the title compound. ¹H NMR (300 MHz,CDCl₃) δ=7.43 (d, J=11.2 Hz, 2H), 7.38 (d, J=11.2 Hz, 2H), 4.36 (d,J=9.0 Hz, 1H), 4.25-4.08 (m, 4H), 4.04 (d, J=8.9 Hz, 1H), 2.86-2.71 (m,1H), 2.46 (td, J=8.1, 13.0 Hz, 1H), 1.58 (s, 6H), 1.21 (t, J=7.2 Hz,3H).

Step 4—(±)-Ethyl2-(4-(3-carbamoyltetrahydrofuran-3-yl)phenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-2-methyl-propanoate (80.0 mg,278 umol) and potassium carbonate (19.2 mg, 139 umol) in N,N-dimethylsulfoxide (5 mL) was added hydrogen peroxide (315 mg, 835 umol, 30%purity, 286 uL) in one portion. The mixture was stirred at rt for 3 hrs.On completion, the mixture was poured into water (30 mL). The solid wascollected by filtration, and dried in vacuo to give the title compound.¹H NMR (300 MHz, CDCl₃) δ=7.29 (d, J=6 Hz, 2H), 7.21 (d, J=6.0 Hz, 2H),5.54-5.20 (m, 2H), 4.38 (d, J=8.7 Hz, 1H), 4.17-3.94 (m, 4H), 3.93-3.81(m, 1H), 2.82-2.68 (m, 1H), 2.26 (td, J=7.5, 12.4 Hz, 1H), 1.55 (s, 6H),1.25 (t, J=6.8 Hz, 3H).

Step 5—(±)-Ethyl2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-2-methyl-propanoate (90.0mg, 295 umol) in acetonitrile (2 mL) and water (2 mL) was addedPhI(CO₂CF₃)₂ (149 mg, 354 umol) in one portion at rt. The reactionmixture was stirred at rt for 16 hrs. On completion, the mixture wasconcentrated in vacuo, and the residue was diluted with water (40 mL)and washed with dichloromethane (2×30 mL). The aqueous phase wasbasified with aqueous sodium hydroxide (1 N) until pH=7-8, and extractedwith ethyl acetate (3×30 mL). The combined organic layers were washedwith brine (30 mL), dried and concentrated in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M-NH2)⁺=261.1, tR=1.228.

(±)-4,5-Dichloro-N-(3-(4-(cyanomethyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide(Intermediate AX)

Step 1—(±)-Ethyl4-(3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-yl)benzoate

To a solution of (±)-ethyl 4-(3-aminotetrahydrofuran-3-yl)benzoate (1.00g, 4.25 mmol) in dichloromethane (10 mL) was added di-tert-butyldicarbonate (1.02 g, 4.68 mmol) and a catalytic amount ofN,N-4-dimethylaminopyridine at rt. The reaction mixture was stirred atrt for 12 hrs. On completion, the reaction mixture was concentrated invacuo. The residue was purified by chromatography (petroleum ether:ethylacetate=30:1 to 10:1) to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=8.02 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 5.22 (br. s.,1H), 4.38 (q, J=7.0 Hz, 2H), 4.12-3.99 (m, 4H), 2.65-2.46 (m, 1H),2.45-2.35 (m, 1H), 1.40 (s, 9H), 1.34-1.21 (t, J=6.8 Hz, 3H).

Step 2—(±)-Tert-butyl(3-(4-(hydroxymethyl)phenyl)tetrahydrofuran-3-yl)carbamate

To a solution of (±)-ethyl4-[3-(tert-butoxycarbonylamino)tetrahydrofuran-3-yl]benzoate (500 mg,1.49 mmol) in anhydrous tetrahydrofuran (10 mL) was added lithiumborohydride (162 mg, 7.45 mmol). The reaction mixture was stirred at rtfor 12 hrs. On completion, the reaction mixture was quenched with water(10 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (2×20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bychromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound. LCMS: (ES⁺) m/z (M-NH₂)⁺=177.2, tR=0.657. ¹H NMR (400 MHz,CDCl3) δ=7.42 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.17 (br. s.,1H), 4.69 (s., 2H), 4.11-4.01 (m, 4H), 2.60-2.45 (m, 1H), 2.44-2.37 (m,1H), 1.38 (s., 9H).

Step 3—(±)-4-(3-((Tert-butoxycarbonyl)amino)tetrahydrofuran-3-yl)benzylmethanesulfonate

To a solution of (±)-tert-butylN-[3-[4-(hydroxymethyl)phenyl]tetrahydrofuran-3-yl]carbamate (599 mg,2.04 mmol) in dichloromethane (20 mL) was addedN,N-dimethylpyridin-4-amine (25.0 mg, 204 umol), triethylamine (413 mg,4.08 mmol) and methanesulfonyl chloride (351 mg, 3.06 mmol) at 0° C. Thereaction mixture was stirred at rt for 12 hrs. On completion, thereaction mixture was diluted with water (20 mL), the organic phase wasseparated, and the aqueous layer was extracted with dichloromethane(3×50 mL). The combined organic layers were washed with brine (20 mL),dried over anhydrous sodium sulfate and concentrated in vacuo to givethe title compound. LCMS: (ES⁺) m/z (M+23)⁺=394.1, tR=0.760.

Step 5—(±)-Tert-butyl(3-(4-(cyanomethyl)phenyl)tetrahydrofuran-3-yl)carbamate

To a solution of(±)-[4-[3-(tert-butoxycarbonylamino)tetrahydrofuran-3-yl]phenyl]methylmethanesulfonate (643 mg, 1.73 mmol) in N,N-dimethylformamide (6 mL) wasadded sodium cyanide (129 mg, 2.63 mmol) at rt. The reaction mixture wasstirred at rt for 12 hrs. The resulting mixture was diluted with water(20 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayer was washed with brine (2×20 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound. LCMS: (ES⁺) m/z (M-NH₂)⁺=186.2, (M+23)⁺=325.3, tR=0.769.

Step6—(±)-4,5-Dichloro-N-(3-(4-(cyanomethyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide

To a solution of (±)-tert-butylN-[3-[4-(cyanomethyl)phenyl]tetrahydrofuran-3-yl]carbamate (15.0 mg,49.6 umol) in dichloromethane (2.5 mL) was added trifluoroacetic acid(500 uL, 6.75 mmol). The reaction mixture was stirred at rt for 2 hrs.On completion, the mixture was concentrated in vacuo to give the titleproduct (320 mg, 67.4% purity, 80% yield) as yellow oil. LCMS: (ES⁺) m/z(M-NH₂)⁺=186.2, tR=0.178.

(±) Ethyl1-[4-(3-aminotetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate(Intermediate AY)

Step 1—(±) Ethyl1-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate

To a solution of (±) ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (2.00 g, 7.71 mmol) inN, N-dimethylformamide (40 mL) was added LiHMDS (1 M, 30.8 mL) dropwiseat rt. The mixture was stirred at the same temperature for 30 mins then1,2-dibromoethane (2.17 g, 11.5 mmol) dissolved in N,N-dimethylformamide (10 mL) was added dropwise at rt. The mixture wasstirred at rt for 2.5 hrs. On completion, the reaction mixture waspoured into 30 mL of iced saturated ammonium chloride solution, and theresulting suspension was extracted with ethyl acetate (3×40 mL). Theorganic phase was collected, dried over anhydrous sodium sulfate, andconcentrated in vacuo to get a residue. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=20:1 to 10:1) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=286.2, tR=0.826. ¹H NMR(400 MHz, CD₃Cl) δ=7.40-7.31 (m, 4H), 4.23 (d, J=9.0 Hz, 1H), 4.07-4.01(m, 2H), 3.97 (q, J=7.2 Hz, 2H), 3.92-3.87 (m, 1H), 2.69-2.61 (m, 1H),2.33 (td, J=8.1, 13.0 Hz, 1H), 1.51-1.46 (m, 2H), 1.07-1.01 (m, 5H).

Step 2—(±) Ethyl1-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate

To a solution of (I) ethyl1-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate (800mg, 2.80 mmol) in dimethyl sulfoxide (8 mL) was added potassiumcarbonate (193 mg, 1.40 mmol). Then, hydrogen peroxide (952 mg, 8.40mmol, 30% wt in water, 807 uL) was added to the resulting mixturedropwise. The mixture was stirred at rt for 3 hrs. On completion, thereaction mixture was poured into 30 mL of ice water, during which a finewhite solid precipitate was formed. The white solid was filtered, andthe filter cake was dried in vacuo to give the title compound. ¹H NMR(400 MHz, CD₃Cl) δ=7.26 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 5.45(br. s., 2H), 4.37 (d, J=8.8 Hz, 1H), 4.07-3.96 (m, 4H), 3.88 (dt,J=5.5, 8.3 Hz, 1H), 2.76 (ddd, J=5.6, 7.5, 12.7 Hz, 1H), 2.30-2.21 (m,1H), 1.56-1.50 (m, 2H), 1.13-1.08 (m, 5H).

Step 3—(±) Ethyl1-[4-(3-aminotetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate

To a solution of (±) ethyl1-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]cyclopropanecarboxylate(650 mg, 2.14 mmol) in acetonitrile (10 mL) and water (10 mL) was added[phenyl-(2,2,2-trifluoroacetyl)oxy-iodanyl] 2,2,2-trifluoroacetate (1.01g, 2.35 mmol). The mixture was stirred at rt for 3 hrs. On completion,the reaction mixture was concentrated in vacuo to remove acetonitrile.The residue was diluted with 0.5 M hydrochloric acid (20 mL) and washedwith ethyl acetate (2×20 mL). The combined inorganic phase layer wasbasified with saturated sodium bicarbonate solution until the pH=8,which was then extracted with dichloromethane (2×20 mL). The combinedorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z(M-NH₂)⁺=259.1, tR=0.554.

(±)-(2-Ethoxy-2-oxoethyl)zinc(II) bromide (Intermediate AZ)

To a mixture of zinc powder (11.8 g, 180 mmol) in anhydroustetrahydrofuran (44 mL) was added chlorotrimethylsilane (976 mg, 8.98mmol) in one portion at rt under nitrogen. Then a solution of ethyl2-bromoacetate (15.0 g, 89.8 mmol) in anhydrous tetrahydrofuran (110 mL)was added dropwise over 0.5 hour at 40-50° C. After the addition, theresulting mixture was stirred at 40° C. for 1 hour. The resultingsolution was used in the next step directly.

Ethyl 2-(4-(3-aminooxetan-3-yl)phenyl)acetate (Intermediate BA)

Step 1—(±)-2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide

To a solution of oxetan-3-one (2.50 g, 34.6 mmol) and(±)-2-methylpropane-2-sulfinamide (4.20 g, 34.6 mmol) in anhydroustetrahydrofuran (25 mL) was added tetraethoxytitanium (11.1 g, 48.5mmol) dropwise at rt. The reaction mixture was stirred at 50° C. for 3hours. On completion, the reaction mixture was poured into 100 mL coolwater and filtered. The filtrate was extracted with dichloromethane(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtrated and concentrated in vacuo. The residue was purifiedby silica gel chromatography (petroleum ether:ethyl acetate=20:1) togive the title compound. ¹H NMR (400 MHz, CDCl₃) δ=5.83-5.76 (m, 1H),5.70-5.62 (m, 1H), 5.52-5.40 (m, 2H), 1.27 (s, 9H).

Step2—(±)-N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

To a solution of 1-bromo-4-iodo-benzene (2.52 g, 8.90 mmol) in anhydroustetrahydrofuran (30 mL) was added n-BuLi (2.5 M, 4.45 mL) dropwise at−70° C. under nitrogen, during which the temperature was maintainedbelow −60° C. Then the reaction mixture was stirred for 0.5 hour at −70°C. A yellow solid precipitated out during the stirring. To the reactionmixture was then added a solution of(±)-2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.30 g, 7.42mmol) in anhydrous tetrahydrofuran (10 mL) dropwise at −70° C. Theresulting mixture was warmed to rt slowly over a period of 1 hour. Oncompletion, the reaction mixture was quenched with water (20 mL) at 0°C., then the mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give the crude product. The crude product waspurified by column chromatography (petroleum ether:ethyl acetate=10:1 to1:1) to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=7.61 (d,J=6.4 Hz, 2H), 7.59 (d, J=6.4 Hz, 2H), 6.36 (s, 1H), 5.00 (d, J=6.3 Hz,1H), 4.95 (d, J=4 Hz, 1H), 4.90 (d, J=4 Hz, 1H), 4.69 (d, J=6.3 Hz, 1H),1.11 (s, 9H).

Step 3—(±)-Ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]phenyl]acetate

To a mixture of Pd₂(dba)₃ (496 mg, 542 umol), XPhos (517 mg, 1.08 mmol)and (±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(1.80 g, 5.42 mmol) in anhydrous tetrahydrofuran (2 mL) was added asolution of bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.5 M, 50 mL) in anhydroustetrahydrofuran (50 mL) at rt under nitrogen. The reaction mixture washeated to 80° C. and stirred for 1 hour. On completion, the reactionmixture was quenched with hydrochloric acid (0.1 N, 10 mL) and dilutedwith water (50 mL). The mixture was extracted with ethyl acetate (3×50mL). The combined organic layer was washed with brine (30 mL), driedover anhydrous sodium sulfate, then concentrated in vacuo to give thecrude product. The crude product was purified by column chromatography(petroleum ether:ethyl acetate=10:1 to 1:1) to give the title compound.¹H NMR (400 MHz, DMSO-d₆) δ=7.44 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz,2H), 6.29 (brs., 1H), 5.02 (d, J=6.4 Hz, 1H), 4.98 (d, J=6.8 Hz, 1H),4.91 (d, J=6.4 Hz, 1H), 4.69 (d, J=6.4 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H),3.68 (s, 2H), 1.20 (t, J=7.2 Hz, 3H), 1.12 (s, 9H).

Step 4—Ethyl 2-(4-(3-aminooxetan-3-yl)phenyl)acetate

To a solution of (±)-ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]phenyl]acetate (1.00 g,2.95 mmol) in a mixture of tetrahydrofuran (10 mL) and water (10 mL) wasadded iodine (74.9 mg, 295 umol) in one portion at rt under nitrogen.The resulting reaction mixture was stirred at 50° C. for 24 hours. Oncompletion, the reaction mixture was quenched with sodium sulfite (10mL), then extracted with DCM (3×30 mL). The combined organic layer waswashed with sodium bicarbonate (100 mL), followed by brine (100 mL),dried over anhydrous sodium sulfate, and concentrated in vacuo to givethe crude product. The crude product was purified by columnchromatography (petroleum ether:ethyl acetate=5:1 to 1:1) to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ=7.53 (d, J=8.4 Hz, 2H), 7.27(d, J=8.4 Hz, 2H), 4.69 (d, J=6.0 Hz, 2H), 4.64 (d, J=6.0 Hz, 2H), 4.08(q, J=6.9 Hz, 2H), 3.65 (s, 2H), 1.19 (t, J=6.9 Hz, 3H).

Ethyl 4-(3-aminooxetan-3-yl)-3-fluoro-benzoate (Intermediate BB)

Step1—(±)-N-[3-(4-bromo-2-fluoro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(3)

To a mixture of 4-bromo-2-fluoro-1-iodo-benzene (CAS #105931-73-5, 20.6g, 68.5 mmol) in tetrahydrofuran (200 mL) was added a solution ofn-BuLi/hexane (2.5 M, 34.24 mL) dropwise at −70° C. under nitrogenatmosphere. The resultant mixture was stirred for 30 min, then to thesolution was added a solution of2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (10.0 g, 57.1 mmol)in tetrahydrofuran (100 mL) dropwise. The mixture was warmed to −20° C.and stirred for 2 hrs. On completion, to the mixture was added ammoniumchloride solution (50 mL, sat.), and the mixture was extracted withethyl acetate (3×100 mL). The combined organic phase was washed withbrine (300 mL), dried over sodium sulfate, and concentrated in vacuo togive a residue. The residue was purified by column chromatography(petroleum ether:ethyl acetate=10:1 to 2:1) to give the title compound.¹HNMR (400 M, DMSO-d₆) δ=7.61 (dd, J=10.4, 1.6 Hz, 1H), 7.52 (dd, J=8.4,1.6 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 6.47 (br, s, 1H), 5.14 (d, J=6.8Hz, 1H), 4.99 (d, J=6.0 Hz, 1H), 4.93 (d, J=6.4 Hz, 2H), 1.11 (s, 9H).

Step 2—(±)-Ethyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-fluoro-benzoate

To a solution of(±)-N-[3-(4-bromo-2-fluoro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(1.00 g, 1.71 mmol) in ethanol (40 mL) was added Pd(dppf)Cl₂ (188 mg,256 umol) and triethylamine (866 mg, 8.57 mmol) under nitrogen. Themixture was stirred under carbon monoxide (50 psi) at 80° C. for 16 hrs.On completion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to get a residue. The residue was purified bychromatography (dichloromethane:methanol=50:1 to 20:1) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=344.1, tR=1.276.

Step 3—Ethyl 4-(3-aminooxetan-3-yl)-3-fluoro-benzoate

A solution of hydrogen chloride in dioxane (4 M, 502 uL) was added intoa solution of the (±)-ethyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-fluoro-benzoate (460 mg,1.34 mmol) in ethanol (1 mL) at 0° C. The mixture was stirred at 0° C.for 1 min. On completion, the reaction mixture was concentrated invacuo. The residue was triturated with methyl tert-butyl ether (30 mL).The precipitate was filtered and dried in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M-NH₂)⁺=223.1, tR=0.413.

Ethyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)acetate (Intermediate BC)

Step 1—(±)-Ethyl2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)-3-fluorophenyl)acetate

To a mixture of Pd₂(dba)₃ (262 mg, 286 umol), XPhos (273 mg, 572 umol)and(±)-N-[3-(4-bromo-2-fluoro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(1.00 g, 2.86 mmol, synthesized via Step 1 of Intermediate BB) intetrahydrofuran (5 mL) was added a solution ofbromo-(2-ethoxy-2-oxo-ethyl)zinc in tetrahydrofuran (0.5 M, 20 mL). Thereaction mixture was stirred at 80° C. for 3 hrs. On completion, themixture was quenched with water (50 mL). The mixture was filtered andthe filtrate was extracted with ethyl acetate (3×30 mL). The combinedorganic layers were washed with brine (50 mL), dried over sodiumsulfate, and concentrated in vacuo. The residue was purified bychromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to give thetitle compound. ¹H NMR (300 MHz, DMSO-d6) δ=7.37 (t, J=8.4 Hz, 1H), 7.15(s, 1H), 7.12 (d, J=2.7 Hz, 1H), 6.37 (s, 1H), 5.12 (d, J=6.6 Hz, 1H),4.96 (d, J=6.6 Hz, 1H), 4.88 (t, J=6.6 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H),3.72 (s, 2H), 1.17-1.21 (t, 3H), 1.04 (s, 9H).

Step 2—Ethyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)acetate

To a mixture of (±)-ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-fluoro-phenyl]acetate(560 mg, 1.57 mmol) in tetrahydrofuran (5 mL) and water (1.5 mL) wasadded iodine (79.7 mg, 314 umol) in one portion at rt. The mixture wasstirred at 50° C. for 24 hrs. On completion, the mixture was quenchedwith saturated aqueous sodium sulfite (20 mL) and extracted with ethylacetate (60 mL). The combined organic layer was washed with brine (30mL), dried over sodium sulfate, and concentrated in vacuo. The residuewas purified by chromatography (petroleum ether:ethyl acetate=10:1 to1:1) to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=7.30 (t,J=8.8 Hz, 1H), 7.08-7.03 (m, 2H), 4.91 (d, J=5.2 Hz, 2H), 4.57 (d, J=6.0Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.70 (s, 2H), 1.20 (t, J=7.2 Hz, 3H).

Ethyl 4-(3-aminooxetan-3-yl)-3-chlorobenzoate (Intermediate BD)

Step1—(±)-N-(3-(4-bromo-2-chlorophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

To a solution of 4-bromo-2-chloro-1-iodobenzene (7.77 g, 24.5 mmol) intetrahydrofuran (60 mL) was added n-butyllithium (8.90 mL, 2.5 M) at−78° C. The mixture was stirred at −70° C. for 1 h, then(±)-2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (3.90 g, 22.25mmol) in tetrahydrofuran (20 mL) was added. The reaction mixture wasstirred at −78° C. for 1 h, then at rt for 4 hrs. On completion, themixture was quenched with saturated aqueous ammonia chloride (20 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by chromatography (dichloromethane:methanol=50:1)to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=365.9, tR=0.888.

Step 2—(±)-Ethyl3-chloro-4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)benzoate

A mixture of(±)-N-[3-(4-bromo-2-chloro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(500 mg, 1.36 mmol), Pd(dppf)Cl₂ (111 mg, 136 umol) and triethylamine(688 mg, 6.80 mmol) in ethanol (12 mL) was stirred at 80° C. undercarbon monoxide (50 Psi) for 12 hrs. On completion, the mixture wasconcentrated. The residue was purified by chromatography (petroleumether:ethyl acetate=1:1) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=360.2, tR=0.791.

Step 3—Ethyl 4-(3-aminooxetan-3-yl)-3-chlorobenzoate

To a solution of (±)-ethyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-chloro-benzoate (340 mg,945 umol) in ethanol (1 mL) was added hydrochloric acid/dioxane (4 M,354 uL) at 0° C., then the mixture was stirred at 0° C. for 10 min. Oncompletion, the reaction solvent was removed by bubbling with nitrogen.The residue was triturated with tert-butyl methyl ether (5 mL). Theresulting solid was collected by filtration and washed with tert-butylmethyl ether (2 mL) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=256.0, tR=0.526.

Ethyl 2-(4-(3-aminooxetan-3-yl)-3-chlorophenyl)acetate (Intermediate BE)

Step 1—(±)-Ethyl2-(3-chloro-4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenyl)acetate

To a mixture of(±)-N-[3-(4-bromo-2-chloro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(700 mg, 1.91 mmol, made via Step 1 of Intermediate BD), Pd₂(dba)₃ (175mg, 191 umol), XPhos (137 mg, 287 umol) in tetrahydrofuran (20 mL) wasadded bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.5 M, 5 mL). The reactionmixture was stirred at 70° C. for 2 hrs. On completion, the mixture wasquenched with saturated ammonium chloride (20 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography (dichloromethane:methanol=30:1) to give thetitle product. LCMS: (ES⁺) m/z (M+H)⁺=374.0, tR=0.751.

Step 2—Ethyl 2-(4-(3-aminooxetan-3-yl)-3-chlorophenyl)acetate

To a solution of (±)-ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-chloro-phenyl]acetate(300 mg, 802 umol) in ethanol (1 mL) was added hydrogen chloride/dioxane(4 M, 300 uL) at 0° C. The reaction mixture was stirred at 0° C. for 1min. On completion, the mixture was concentrated in vacuo to give thetitle product (150 mg, 69% yield) as yellow oil. LCMS: (ES⁺) m/z(M+H)⁺=270.1, tR=0.566.

Ethyl 4-(3-aminooxetan-3-yl)-3-methylbenzoate (Intermediate BF)

Step1—(±)-N-(3-(4-bromo-2-methylphenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

To a solution of 4-bromo-1-iodo-2-methyl-benzene (3.73 g, 12.6 mmol) inanhydrous tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M, 5.02mL) at −70° C. for 30 min. Then,(±)-2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (2.00 g, 11.4mmol) in anhydrous tetrahydrofuran (10 mL) was added at −70° C. Thereaction mixture was stirred at rt for 30 min. On completion, themixture was quenched with water (20 mL) and concentrated in vacuo toremove the organic solvent. The aqueous phase was extracted withdichloromethane (3×100 mL) and the combined organic layers were driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography (dichloromethane:methanol=100:1) to give thetitle compound. ¹H NMR (400 MHz, CDCl3) δ=7.42-7.30 (m, 2H), 7.04 (d,J=8.0 Hz, 1H), 5.33 (d, J=7.0 Hz, 1H), 5.15 (d, J=6.8 Hz, 1H), 5.02 (d,J=6.8 Hz, 1H), 4.90 (d, J=7.0 Hz, 1H), 4.24 (s, 1H), 2.13 (s, 3H), 1.19(s, 9H).

Step 2—(±)-Ethyl4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)-3-methylbenzoate

To a solution of(±)-N-[3-(4-bromo-2-methyl-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(500 mg, 1.44 mmol) and triethylamine (729 mg, 7.20 mmol) in ethanol (10mL) was added Pd(dppf)Cl₂ (118 mg, 144 umol) in one portion undernitrogen. The mixture was stirred under carbon monoxide (50 psi) at 80°C. for 16 hrs. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by chromatography(petroleum ether:ethyl acetate=10:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=340.2, tR=0.766.

Step 3—Ethyl 4-(3-aminooxetan-3-yl)-3-methylbenzoate

To a solution of ethyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-methyl-benzoate (188 mg,554 umol) in ethanol (2 mL) was added hydrogen chloride/dioxane (4 M,208 uL) at 0° C. The reaction mixture was stirred at 0° C. for 1 min. Oncompletion, the mixture was concentrated in vacuo. The residue wastriturated with methyl tert-butyl ether (2 mL) and the solid wascollected by filtration to give the title compound. LCMS: (ES⁺) m/z(M-NH₂)⁺=219.1, tR=0.512.

Ethyl 2-(4-(3-aminooxetan-3-yl)-3-methylphenyl)acetate (Intermediate BG)

Step 1—Ethyl2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)-3-methylphenyl)acetate

To a suspension of Pd₂(dba)₃ (146 mg, 159 umol) and Xphos (152 mg, 318umol) in anhydrous tetrahydrofuran (5 mL) was addedN-[3-(4-bromo-2-methyl-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(550 mg, 1.59 mmol, synthesized via Step 1 of Intermediate BF) undernitrogen. Then, (2-ethoxy-2-oxoethyl)zinc(II) bromide (0.5 M, 30 mL) wasadded dropwise to the reaction mixture at rt. The reaction mixture wasstirred at 70° C. for 2.5 hrs. On completion, the reaction mixture wasquenched with water (20 mL). The mixture was filtered, and the filtratewas concentrated in vacuo to remove the tetrahydrofuran. Then, theresidue was extracted with ethyl acetate (3×50 mL), dried over anhydroussodium sulfate, and concentrated in vacuo to give a residue. The residuewas purified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to give the title compound. LCMS: (ES⁺) m/z (M+1)⁺=354.3,tR=0.757.

Step 2—Ethyl 2-(4-(3-aminooxetan-3-yl)-3-methylphenyl)acetate

To a solution of ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-methyl-phenyl]acetate(120 mg, 340 umol) in ethanol (1.5 mL) was added HCl/dioxane (4 M, 127uL) at 0° C. The reaction mixture was stirred 10 min. On completion, thereaction was concentrated in vacuo to give a residue. The residue wastriturated with methyl tert-butyl ether (2 mL) and filtered to affordthe title compound. LCMS: (ES⁺) m/z (M-NH₂)⁺=233.1, tR=0.512.

4-Bromo-1-iodo-2-methoxybenzene (Intermediate BH)

To a solution of 5-bromo-2-iodo-phenol (1.00 g, 3.35 mmol) in acetone(10.0 mL) was added iodomethane (951 mg, 6.70 mmol) and anhydrouspotassium carbonate (926 mg, 6.70 mmol) at rt. The reaction mixture wasstirred at rt for 12 hrs. On completion, the reaction mixture wasfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether) to give thetitle compound (1.00 g, 96% yield). ¹H NMR (400 MHz, CDCl3) δ=7.61 (d,J=8.4 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.87 (dd, J=8.4 Hz, 1.8 Hz, 1H),3.89 (s, 3H).

Ethyl 2-(4-(3-aminooxetan-3-yl)-3-methoxyphenyl)acetate (IntermediateBI)

Step1—(±)-N-(3-(4-bromo-2-methoxyphenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

To a solution of 4-bromo-1-iodo-2-methoxy-benzene (642 mg, 2.05 mmol) inanhydrous tetrahydrofuran (5 mL) was added n-BuLi (2.5 M, 820 uL) at−70° C. under a nitrogen for 30 min. Then,(±)-2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (360 mg, 2.05mmol) in anhydrous tetrahydrofuran (5 mL) was added at −70° C. under anitrogen for 30 min. The reaction mixture was stirred at 25° C. for 30min. On completion, the reaction was quenched with saturated ammoniumchloride (8 mL) and concentrated in vacuo to remove tetrahydrofuran. Theresidue was extracted with ethyl acetate (3×20 mL), dried over anhydroussodium sulfate and concentrated in vacuo. The yellow oil was purified bysilica gel chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) togive the title compound. LCMS: (ES⁺) m/z (M+1)⁺=362.1, tR=0.777.

Step 2—(±)-Ethyl2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)-3-methoxyphenyl)acetate

To a suspension of Pd₂(dba)₃ (55.6 mg, 60.7 umol) and Xphos (57.9 mg,121 umol) in anhydrous tetrahydrofuran (3 mL) was added(±)-N-[3-(4-bromo-2-methoxy-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(220 mg, 607 umol) under nitrogen. Then,bromo-(2-ethoxy-2-oxo-ethyl)zinc (1 M/L, 607 uL, 607 umol) was addeddropwise at rt for 0.5 hr. The reaction mixture was stirred at 70° C.for 2.5 hrs. On completion, the reaction mixture was diluted with water(20 mL), filtered, and the filtrate was extracted with ethyl acetate(3×50 mL). The combined organic layer was dried over anhydrous sodiumsulfate and concentrated in vacuo to give the residue. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=1:1) to give the title compound. LCMS: (ES⁺) m/z (M+1)⁺=370.3,tR=0.765.

Step 3—Ethyl 2-(4-(3-aminooxetan-3-yl)-3-methoxyphenyl)acetate

To a solution of (±)-ethyl2-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]-3-methoxy-phenyl]acetate(120 mg, 325 umol) in ethanol (1 mL) was added HCl/dioxane (4 M, 122 uL)at 0° C. The reaction mixture was stirred for 0.5 hr. On completion, thereaction was concentrated in vacuo to give a residue. The residue wastriturated with methyl tert-butyl ether (2 mL) and filtered to affordthe title compound. LCMS: (ES⁺) m/z (M-NH₂)⁺=249.2, tR=0.577.

(±)-Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)-3-fluorophenyl)propanoate(Intermediate BJ) & (±)-Ethyl2-(4-(3-aminotetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate(Intermediate BK)

Step 1—(±)-3-(4-Bromo-2-fluorophenyl)tetrahydrofuran-3-carbonitrile

A solution of sodium hydride (1.01 g, 42.06 mmol) in dimethyl formamide(20.0 mL) was stirred at −5° C. Then a solution of2-(4-bromo-2-fluoro-phenyl)acetonitrile (3.00 g, 14.02 mmol) and1-chloro-2-(chloromethoxy)ethane (2.17 g, 16.82 mmol) in dimethylformamide (10.0 mL) was added dropwise at −5° C., and the mixture wasstirred at −5-10° C. for 4 hrs. On completion, the mixture was pouredinto water (60 mL) then the aqueous phase was extracted with ethylacetate (3×30 mL). The combined extracts were washed with brine (30 mL),dried and concentrated to give a yellow oil. The mixture was purified bycolumn chromatography (petroleum ether:ethyl acetate=20:1 to 10:1) togive the title compound. ¹HNMR (400 MHz, CDCl₃) δ=7.42-7.28 (m, 3H),4.49 (dd, J=2.3, 9.0 Hz, 1H), 4.22 (q, J=7.6 Hz, 1H), 4.10 (dt, J=4.9,8.5 Hz, 1H), 4.03 (d, J=9.0 Hz, 1H), 2.85-2.74 (m, 1H), 2.54 (td, J=7.8,12.8 Hz, 1H)

Step 2—(±)-Ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)-3-fluorophenyl)acetate

A solution of(±)-3-(4-bromo-2-fluoro-phenyl)tetrahydrofuran-3-carbonitrile (3.40 g,12.59 mmol), dimethylaminopyridine (153.79 mg, 1.26 mmol), 1.1′-alnaphthalene-2.2-diphenyl phosphine (783.81 mg, 1.26 mmol), andallyl(chloro)palladium (115.15 mg, 629.50 umol) in xylene (50.0 mL) wasstirred at rt for 30 min under nitrogen. Then(3-ethoxy-3-oxo-propanoyl)oxypotassium (1.04 g, 6.11 mmol) was added inone portion and the reaction mixture was stirred at 140° C. for 16 hrs.On completion, ethyl acetate (100 mL) was added to the mixture, and thenthe solution was washed with water (2×30 mL), brine (1×30 mL), dried andconcentrated. The mixture was purified by column chromatography(petroleum ether:ethyl acetate=20:1 to 10:1) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ=7.42-7.36 (m, 1H), 7.08-7.16 (m, 2H), 4.51(dd, J=9.0, 2.3 Hz, 1H), 4.13-4.27 (m, 4H), 4.03 (d, J=8.8 Hz, 1H), 3.63(s, 2H), 2.75-2.85 (m, 1H), 2.57 (dt, J=12.8, 7.9 Hz, 1H), 1.28 (t,J=7.2 Hz, 3H).

Step 3—(±)-Ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)-3-fluorophenyl)propanoate & (±)-ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)-3-fluoro-phenyl]acetate (1.49 g, 5.37mmol) in tetrahydrofuran (20.0 mL) was added LiHMDS (1.0 M, 8.59 mL)dropwise at −10° C. After the mixture was stirred at −10° C. for 30 min,iodomethane (762.71 mg, 5.37 mmol, 334.52 uL) was added dropwise at −10°C., then the mixture was stirred at −10˜rt for 2 hrs. On completion, themixture was poured into water (80 mL), extracted with ethyl acetate(2×30 mL), washed with brine (20 mL), dried and concentrated to give thetitle compounds as mixture of the mono and bis addition products.

Step 4—(±)-Ethyl2-(4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluorophenyl)propanoate &(±)-ethyl2-(4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)-3-fluoro-phenyl]propanoate &(±)-ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate (amixture) (1.40 g, 4.81 mmol) and potassium carbonate (332 mg, 2.40 mmol)in dimethyl sulfoxide (10 mL) was added hydrogen peroxide (5.45 g, 48.1mmol) in one portion. Then the mixture was stirred at rt for 3 hours. Oncompletion, the mixture was poured into water (60 mL), filtered, anddried in vacuo to give the title compounds (mixture). LCMS: (ES⁺) m/z(M+H)⁺=310.1; 324.1, tR=1.384.

Step 5—(±)-Ethyl2-(4-(3-aminotetrahydrofuran-3-yl)-3-fluorophenyl)propanoate (BJ)(±)-ethyl2-(4-(3-aminotetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate(BK)

To a solution of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluoro-phenyl]propanoate &(±)-ethyl2-(4-(3-carbamoyltetrahydrofuran-3-yl)-3-fluorophenyl)-2-methylpropanoate(mixture) (1.30 g, 4.20 mmol) in acetonitrile (10 mL) and water (10 mL)was added PhI(CF₃CO₂)₂ (2.12 g, 5.04 mmol) in one portion at rt. Thenthe mixture was stirred at rt for 16 hours. On completion, theacetonitrile was removed in vacuo, and the residue was diluted withwater (50 mL) and acidified by hydrochloric acid (2 N) until pH=2. Thenthe mixture was washed with dichloromethane (2×20 mL), the aqueous phasewas basified with 1M sodium hydroxide to pH=7-8, and the mixture wasextracted with ethyl acetate (3×20 mL). The combined organic extractswere washed with brine (20 mL), dried and concentrated to give the titlecompounds (a mixture of the mono and bis addition products). LCMS: (ES⁺)m/z (M-NH₂)⁺=265.1; 296.1, tR=1.391.

(±)-Ethyl 2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]butanoate(Intermediate BL)

Step 1—(±)-Ethyl 2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]butanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (500 mg, 1.93 mmol) intetrahydrofuran (10 mL) was added LiHMDS (1 M, 2.32 mL) dropwise at 0°C. After stirring at 0° C. for 0.5 hr, ethyl iodide (300 mg, 1.93 mmol)was added into the mixture. The resulting mixture was slowly warmed tort and stirred at rt for 2 hrs. On completion, the mixture was quenchedwith ammonium chloride solution (10 mL), diluted with water (50 mL) andextracted with ethyl acetate (3×40 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.38-7.32 (m, 2H),7.28 (d, J=8.3 Hz, 2H), 4.29 (d, J=9.0 Hz, 1H), 4.16-4.07 (m, 3H),4.07-3.99 (m, 1H), 3.96 (d, J=8.8 Hz, 1H), 3.38 (t, J=7.7 Hz, 1H),2.80-2.63 (m, 1H), 2.38 (td, J=8.2, 12.9 Hz, 1H), 2.10-1.92 (m, 1H),1.71 (m, 14.1 Hz, 1H), 1.15 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H).

Step 2—(±)-Ethyl 2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]butanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]butanoate (500 mg, 1.74 mmol)and potassium carbonate (96.2 mg, 696 umol) in dimethyl sulfoxide (10mL) was added hydrogen peroxide (1.58 g, 13.9 mmol). The mixture wasstirred at 50° C. for 3 hrs. On completion, the mixture was quenchedwith sodium sulfite solution (20 mL) and extracted with ethyl acetate(2×60 mL). The organic layer was then washed with water (50 mL), brine(50 mL), and the combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=306.2, tR=0.777.

Step 3—(±)-Ethyl 2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]butanoate

To a mixture of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]butanoate (530 mg, 1.74mmol) in acetonitrile (8 mL) and water (8 mL) was added PhI(O₂CCF₃)₂(823 mg, 1.91 mmol) in one portion, and the mixture was stirred at rtfor 16 hrs. On completion, the mixture was concentrated in vacuo. 1N HCl(8 mL) was added into the mixture and the mixture was extracted withethyl acetate (50 mL). The aqueous layer was then basified with sodiumbicarbonate to pH=9, and extracted with dichloromethane (2×60 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=7.44-7.38 (m, 2H), 7.35-7.30 (m, 2H), 4.24-4.05 (m, 4H),3.96-3.92 (m, 1H), 3.91-3.86 (m, 1H), 3.46 (t, J=7.7 Hz, 1H), 2.40 (td,J=8.9, 12.5 Hz, 1H), 2.20-2.05 (m, 2H), 1.87-1.77 (m, 1H), 1.24 (t,J=7.2 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).

(±)-Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)propanoate(Intermediate

Step 1—(±)-Ethyl 2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)propanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (650 mg, 2.51 mmol) intetrahydrofuran (20 mL) was added lithium bis(tert-butylsilyl)amide (1M, 3.01 mL) at 0° C. The mixture was stirred at 0° C. for 1 hr beforeiodomethane (392 mg, 2.76 mmol) was added, then the mixture was stirredat rt for 1 hr. On completion, the mixture was quenched with saturatedaqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3×10mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography (petroleum ether:ethyl acetate=5:1) to give the titleproduct. ¹H NMR (400 MHz, CDCl₃) δ=7.49-7.43 (m, 2H), 7.39-7.34 (m, 2H),4.38 (d, J=9.0 Hz, 1H), 4.22-4.09 (m, 4H), 4.05 (d, J=9.0 Hz, 1H), 3.74(q, J=7.3 Hz, 1H), 2.84-2.76 (m, 1H), 2.48 (m, 1H), 1.52 (d, J=7.0 Hz,3H), 1.24 (t, J=7.2 Hz, 3H).

Step 2—(±)-Ethyl 2-(4-(3-carbamoyltetrahydrofuran-3-yl)phenyl)propanoate

To a mixture of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]propanoate (500 mg, 1.83 mmol)and potassium carbonate (101 mg, 732 umol) in dimethyl sulfoxide (2 mL)was added hydrogen peroxide (830 mg, 7.32 mmol, 30% purity). The mixturewas stirred at rt for 1 hr. On completion, the reaction was quenchedwith water (5 mL) where a precipitate formed. The resulting solid wascollected by filtration and washed with water (5 mL) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=292.1, tR=0.646.

Step 3—(±)-Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)propanoate

To a solution of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]propanoate (200 mg, 686umol) in acetonitrile (4 mL) and water (4 mL) was added(diacetoxyiodo)benzene (243 mg, 755 umol). The mixture was stirred at rtfor 1 hr. On completion, the mixture was acidified by hydrochloric acid(2 N) until pH=2, then washed with ethyl acetate (3×5 mL). The aqueouslayer was separated, basified with aqueous sodium hydroxide (2 N) untilpH=11, and extracted with ethyl acetate (3×5 mL). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo to give the title product. LCMS: (ES⁺) m/z (M-NH2)⁺=247.1,tR=0.546.

(±)-Ethyl 2-[4-(3-aminooxetan-3-yl)phenyl]propanoate (Intermediate BN)

Step1—(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)-propane-2-sulfinamide

To a solution of(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(17.0 g, 51.1 mmol, synthesized via Steps 1-2 of Intermediate BA) intetrahydrofuran (300 mL) was added sodium hydride (4.09 g, 102 mmol,60%) at 0° C. and the reaction mixture was stirred for 0.5 hr. ThenSEMCI (12.8 g, 76.7 mmol) was added dropwise and the reaction mixturewas stirred at rt for 0.5 hr. On completion, the reaction mixture waspoured into 1000 mL ice-water. The aqueous phase was then extracted withdichloromethane (3×1000 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. The solidwas purified by silica gel chromatography (petroleum ether:ethylacetate=5:1) to give title compound. ¹H NMR (400 MHz, CDCl3) δ=7.61-7.49(m, 4H), 5.38 (d, J=6.4 Hz, 1H), 5.26 (d, J=6.8 Hz, 1H), 4.84 (d, J=6.4Hz, 1H), 4.72 (d, J=10.7 Hz, 1H), 4.68 (d, J=10.5 Hz, 1H), 3.82 (d,J=10.5 Hz, 1H), 3.39-3.31 (m, 2H), 1.37 (s, 9H), 0.93-0.85 (m, 2H), 0.02(s, 9H).

Step 2—(±)-Ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate

To a solution of(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide(16.0 g, 34.5 mmol), XPhos (3.30 g, 6.92 mmol) and Pd₂(dba)₃ (3.17 g,3.46 mmol) in tetrahydrofuran (250 mL) was added a solution ofbromo-(2-ethoxy-2-oxo-ethyl)zinc (0.8 M, 64.86 mL) in tetrahydrofuran(140 mL) and the reaction mixture was stirred at 75° C. for 1 hr. Oncompletion, the reaction mixture was quenched with 70 mL ammoniumchloride saturated solution and filtered. The filtrate was extractedwith ethyl acetate (3×500 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (petroleumether:ethyl acetate=5:1) to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=7.58 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 5.37 (d, J=6.3Hz, 1H), 5.25 (d, J=6.7 Hz, 1H), 4.89 (d, J=6.3 Hz, 1H), 4.77 (d, J=10.5Hz, 1H), 4.70 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.85 (d, J=10.5 Hz, 1H),3.63 (s, 2H), 3.34 (t, J=8.1 Hz, 2H), 1.36 (s, 9H), 1.21 (t, J=7.2 Hz,3H), 0.89 (dd, J=7.3, 8.9 Hz, 2H), 0.01 (s, 9H).

Step 3—(±)-Ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]propanoate

To a solution of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (800 mg, 1.70 mmol) in tetrahydrofuran (20.0 mL) wasadded LDA (2 M, 1.53 mL) dropwise at 0° C. and the reaction mixture wasstirred for 0.5 hr. Then methyl iodide (241 mg, 1.70 mmol) intetrahydrofuran (1 mL) was added and the reaction mixture was stirred atrt for 0.5 hr. On completion, the reaction mixture was poured into 30 mLcool water and acidified with citric acid solution until pH=6-7. Theaqueous phase was extracted with dichloromethane (3×30 mL), dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. Theresulting oil was purified by silica gel chromatography (petroleumether:ethyl acetate=10:1) to give the title compound. ¹HNMR (400 MHz,CDCl3) δ=7.58 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 5.38 (d, J=6.1Hz, 1H), 5.25 (d, J=6.7 Hz, 1H), 4.89 (d, J=6.3 Hz, 1H), 4.74 (d, J=6.8Hz, 1H), 4.72 (dd, J=1.3, 10.5 Hz, 1H), 4.20-4.08 (q, J=7.1 Hz, 2H),3.85 (dd, J=1.3, 10.5 Hz, 1H), 3.73 (q, J=7.2 Hz, 1H), 3.35 (t, J=8.2Hz, 2H), 1.51 (d, J=7.2 Hz, 3H), 1.37 (s, 9H), 1.23 (t, J=7.2 Hz, 3H),0.92-0.85 (m, 2H), 0.01 (s, 9H).

Step 4—(±)-Ethyl 2-[4-(3-aminooxetan-3-yl)phenyl]propanoate

To a solution of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]propanoate (700 mg, 1.45 mmol) in ethanol (8 mL) was addedhydrochloric acid/dioxane (4 M, 3.62 mL) and the reaction mixture wasstirred at 0° C. for 30 min. On completion, the reaction mixture wasbasified with saturated sodium bicarbonate solution until pH=8 andextracted with dichloromethane (3×20 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtrated and concentrated in vacuoto give the title compound (400 mg, crude) as light yellow oil. LCMS:(ES⁺) m/z (M-NH2)⁺=233.1, tR=1.024.

(±)-Ethyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)propanoate(Intermediate BO) & Ethyl2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate(Intermediate BP)

Step1—(±)-N-(3-(4-Bromo-2-fluorophenyl)oxetan-3-yl)-2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propane-2-sulfinamide

To a solution of(±)-N-[3-(4-bromo-2-fluoro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(3.00 g, 8.57 mmol, synthesized via Step 1 of Intermediate BB) intetrahydrofuran (30.0 mL) was added sodium hydride (685 mg, 17.1 mmol)in portions at −10° C., and the resultant mixture was stirred for 30min. Then, 2-(chloromethoxy)ethyl-trimethyl-silane (2.86 g, 17.1 mmol)was added dropwise. The mixture was warmed to 30° C. with stirring for16 hrs. On completion, the reaction mixture was quenched with water (50mL) and extracted with ethyl acetate (3×50 mL). The combined organicphase was washed by brine (100 mL), dried over sodium sulfate, andconcentrated in vacuo to give the crude product. The crude product waspurified by column chromatography (petroleum ether:ethyl acetate=20:1 to10:1) to give the title compound (1.7 g, yield 37%). ¹H NMR (300 MHz,CDCl₃) δ=7.33-7.18 (m, 3H), 5.22 (d, J=7.2 Hz, 1H), 5.16 (d, J=7.5 Hz,1H), 5.04-5.08 (m, 2H), 4.53 (d, J=10.5 Hz, 1H), 4.14 (d, J=10.8 Hz,1H), 3.44-3.28 (m, 2H), 1.24 (s, 9H), 0.86 (t, J=8.1 Hz, 2H), 0.00 (s,9H).

Step 2—(±)-Ethyl2-(3-fluoro-4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)acetate

To a mixture of Pd₂(dba)₃ (57.2 mg, 62.4 umol) and XPhos (59.5 mg, 125umol) was added a solution of(±)-N-[3-(4-bromo-2-fluoro-phenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide (300 mg, 624 umol) in tetrahydrofuran (2mL) under nitrogen. Then, a solution of bromo-(2-ethoxy-2-oxo-ethyl)zincin tetrahydrofuran (0.5M, 5.00 mL) was added in one portion at rt. Thereaction mixture was heated to 80° C. and stirred for 2 hrs. Oncompletion, the cooled solution was quenched with water (30 mL), thenfiltered, and the filtrate was extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with brine (50 mL), dried oversodium sulfate, and concentrated in vacuo to give a residue which waspurified by column chromatography (petroleum ether:ethyl acetate=20:1 to5:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.28 (t,J=8.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 5.25 (d,J=7.2 Hz, 1H), 5.20 (d, J=7.2 Hz, 1H), 5.12 (d, J=7.2 Hz, 2H), 4.57 (d,J=10.8 Hz, 1H), 4.21-4.16 (m, 3H), 3.62 (s, 2H), 3.44-3.34 (m, 2H),1.30-1.27 (m, 12H), 0.93-0.89 (m, 2H), 0.027 (s, 9H).

Step 3—(±)-Ethyl2-(3-fluoro-4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)propanoate & Ethyl2-(4-(3-((tert-butylsulfinyl)((2-(trimethylsilyl)ethoxy)methyl)amino)oxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate

To a solution of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]acetate (840 mg, 1.72 mmol) intetrahydrofuran (14.0 mL) was added sodium hydride (103 mg, 2.58 mmol,60% purity) in one portion at 0° C. The mixture was stirred at 0° C. for30 min. Then, a solution of methyl iodide (293 mg, 2.06 mmol) intetrahydrofuran (5.00 mL) was added dropwise at 0° C. After theaddition, the resultant mixture was stirred for 3 hrs. On completion,the mixture was quenched with water (50 mL) and extracted with ethylacetate (3×30 mL). The combined organic phase was dried over sulfate andconcentrated in vacuo to give a residue which was purified by columnchromatography (petroleum ether:ethyl acetate=20:1 to 5:1) to give thetitle compounds (as a mixture of monomethyl and gem-dimethyl) that wereused directly in the next step.

Step 4—(±)-Ethyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)propanoate &Ethyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate

To a mixture of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]propanoate & ethyl2-(4-(3-((tert-butylsulfinyl)((2-(trimethylsilyl)ethoxy)-methyl)amino)oxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate(200 mg, 399 umol) in ethanol (1.00 mL) was added hydrochloride/dioxane(4 M, 498 uL) dropwise at 0° C. The mixture was stirred at 0° C. for 2hrs. On completion, to the mixture was added sodium bicarbonate (sat. 5mL) and the solution was extracted with dichloromethane (3×10 mL). Thecombined organic phase was washed with brine (20 mL), dried over sodiumsulfate, and concentrated in vacuo to give a residue which was purifiedby column chromatography (petroleum ether:ethyl acetate=10:1 to 2:1) togive the title compound as a mixture of the monomethyl and gem-dimethyl.LCMS: (ES⁺) m/z (M-NH2)⁺=251.1, tR=0.629.

(±)-Ethyl 2-[4-(3-aminooxetan-3-yl)-3-chloro-phenyl]propanoate(Intermediate BQ)

Step1—(±)-N-[3-(4-bromo-2-chloro-phenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxy-methyl)propane-2-sulfinamide

To a solution of(±)-N-[3-(4-bromo-2-chloro-phenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(2.00 g, 5.45 mmol, synthesized via Step 1 of Intermediate BD) intetrahydrofuran (30 mL) was added sodium hydride (261 mg, 10.9 mmol) at0° C. and the reaction mixture was stirred for 0.5 hour under nitrogen.Then (2-(chloromethoxy)ethyl) trimethylsilane (1.36 g, 8.18 mmol) wasadded dropwise and the reaction mixture was stirred at rt for 0.5 hour.On completion, the mixture was slowly poured into ice water (100 mL),and extracted with dichloromethane (2×150 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a residue. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=10:1) and concentrated invacuo to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.57 (d,J=2.0 Hz, 1H), 7.45 (dd, J=1.9, 8.4 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H),5.39-5.23 (m, 2H), 5.15 (dd, J=7.7, 12.4 Hz, 2H), 4.69 (d, J=10.8 Hz,1H), 4.34 (d, J=10.5 Hz, 1H), 3.49-3.27 (m, 2H), 1.23 (s, 9H), 0.89 (t,J=8.2 Hz, 2H), 0.03 (s, 9H).

Step 2—(±)-Ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-chloro-phenyl]acetate

To a solution of(±)-N-[3-(4-bromo-2-chloro-phenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide (1.00 g, 2.01 mmol), Pd₂(dba)₃ (184 mg,201 umol) and XPhos (191 mg, 402 umol) in tetrahydrofuran (20 mL) wasadded a solution of bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.6 M, 5.02 mL) intetrahydrofuran (10 mL) and the reaction mixture was stirred at 80° C.for 1 hour under nitrogen. On completion, the mixture was quenched with30 mL water, filtered and extracted with ethyl acetate (3×30 mL). Theorganic layer was dried with anhydrous sodium sulfate, filtrated andconcentrated to give the residue. The crude product was purified byprep-column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1)to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.31 (s, 1H),7.24-7.16 (m, 2H), 5.30 (dd, J=7.5, 14.6 Hz, 2H), 5.20-5.02 (m, 2H),4.66 (d, J=10.5 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 4.16 (q, J=7.0 Hz,2H), 3.59 (s, 2H), 3.46-3.24 (m, 2H), 1.30-1.23 (m, 3H), 1.20 (s, 9H),0.87 (t, J=8.2 Hz, 2H), 0.00 (s, 9H).

Step3—(±)-2-[4-[3-[Tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-chloro-phenyl]propanoate

To a mixture of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-chloro-phenyl]acetate (400 mg, 793 umol) intetrahydrofuran (10 mL) was added lithium diisopropylamide (2 M, 595 uL)at 0° C. Then iodomethane (112 mg, 793 umol) was added to the mixturedropwise at 0° C. The mixture was stirred at rt for 2 hours. Oncompletion, the mixture was quenched with water (30 mL) and extractedwith ethyl acetate (3×30 mL). The organic layer was dried with anhydroussodium sulfate, filtrated and concentrated in vacuo. The residue waspurified by prep-column chromatography (petroleum ether:ethylacetate=3:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.34(s, 1H), 7.25 (s, 2H), 5.33 (dd, J=7.7, 17.7 Hz, 2H), 5.17 (dd, J=7.5,19.3 Hz, 2H), 4.68 (dd, J=2.9, 10.7 Hz, 1H), 4.32 (dd, J=2.3, 10.8 Hz,1H), 4.22-4.04 (m, 2H), 3.71 (q, J=7.3 Hz, 1H), 3.49-3.27 (m, 2H), 1.51(d, J=7.0 Hz, 3H), 1.31-1.24 (m, 3H), 1.23 (s, 9H), 0.90 (t, J=8.2 Hz,2H), 0.03 (s, 9H).

Step 4—(±)-Ethyl 2-[4-(3-aminooxetan-3-yl)-3-chloro-phenyl]propanoate

To a mixture of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-chloro-phenyl]propanoate (300 mg, 579 umol) in ethanol (2mL) was added 4 N hydrochloric acid/dioxane (4 M, 145 uL). Then themixture was stirred at 0° C. for 0.5 hour. On completion, the mixturewas dried by bubbling nitrogen through the mixture. Then the residue wastriturated with 20 mL methyl tert-butyl ether and filtrated to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=284.1, tR=0.652.

(±) Potassium 2-cyanopropanoate (Intermediate BR)

To a solution of (1) ethyl 2-cyanopropanoate (10.0 g, 78.7 mmol, CAS#1572-99-2) in ethanol (50 mL) was added water (1.42 g, 78.7 mmol). Thereaction mixture was stirred at 40° C. for 2 hrs. Then a solution oftert-butoxypotassium (8.83 g, 78.7 mmol) in ethanol (50 mL) was addeddropwise at 40° C. to the mixture over 0.5 hr. The reaction mixture wasstirred at 40° C. for 2 hrs. On completion, the reaction mixture wasconcentrated in vacuo to remove ethanol. The residue was triturated with(ethanol: 2-methoxy-2-methylpropane=1:3; 100 mL), filtered and dried toafford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=3.07 (q, J=7.2Hz, 1H), 1.25 (d, J=7.2 Hz, 3H).

(±) 2-(4-(3-Aminotetrahydrofuran-3-yl)phenyl)propanenitrile(Intermediate BS)

Step 1—(±) Tert-butyl (3-(4-bromophenyl)tetrahydrofuran-3-yl)carbamate

To a solution of (±) 3-(4-bromophenyl)tetrahydrofuran-3-amine (3.20 g,13.2 mmol) in dichloromethane (30 mL) was added di-tert-butyldicarbonate (3.17 g, 14.5 mmol, 3.34 mL) and N,N-dimethylpyridin-4-amine(162 mg, 1.32 mmol) at rt. The reaction mixture was stirred at rt for 12hrs. On completion, the reaction mixture was concentrated in vacuo. Theyellow oil was purified by silica gel chromatography (petroleumether:ethyl acetate=30/1 to 10/1) to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ=7.68 (br. s., 1H), 7.51 (d, J=8.4 Hz, 2H), 7.29 (d,J=8.6 Hz, 2H), 4.04 (d, J=8.8 Hz, 1H), 3.97-3.90 (m, 1H), 3.88-3.82 (m,2H), 2.51-2.49-2.37 (m, 1H), 2.10 (td, J=13.0, 8.2 Hz, 1H), 1.34 (s.,9H).

Step 2—(±) Tert-butyl(3-(4-(1-cyanoethyl)phenyl)tetrahydrofuran-3-yl)carbamate

A solution of (±) tert-butylN-[3-(4-bromophenyl)tetrahydrofuran-3-yl]carbamate (100 mg, 292 umol),Pd₂(allyl)₂Cl₂ (5.35 mg, 14.6 umol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.4 mg, 43.8 umol) inmesitylene (1 mL) was stirred at rt for 0.5 hr under a nitrogen. Then,2-cyanopropanoyloxypotassium (48.1 mg, 351 umol) was added in oneportion and the reaction mixture was stirred at 140° C. for 6 hr. Oncompletion, the reaction mixture was concentrated in vacuo, extractedwith ethyl acetate (3×5 mL), filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.45(d, J=8.5 Hz, 2H), 7.38-7.33 (m, 2H), 5.19 (br. s., 1H), 4.12-4.07 (m,2H), 4.05 (br. s., 2H), 3.91 (q, J=7.3 Hz, 1H), 2.58-2.41 (m, 1H), 2.40(td, J=8.4, 12.8 Hz, 1H), 1.66 (d, J=7.3 Hz, 3H), 1.41 (s, 9H).

Step 3—(±) 2-(4-(3-Aminotetrahydrofuran-3-yl)phenyl)propanenitrile

To a solution of (±) tert-butylN-[3-[4-(1-cyanoethyl)phenyl]tetrahydrofuran-3-yl]carbamate (200 mg, 632umol) in dichloromethane (2 mL) was added trifluoroacetic acid (308 mg,2.70 mmol). The reaction mixture was stirred at rt for 1 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound. LCMS: (ES⁺) m/z (M-NH2)⁺=200.2, tR=0.237.

Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-2-methylpropanoate (IntermediateBT)

Step1—2-[4-[3-[Tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-aceticacid

To a solution of ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (40.0 g, 85.1 mmol, synthesized via Steps 1-2 ofIntermediate BN) in a mixture of water (150 mL) and tetrahydrofuran (300mL) was added lithium hydroxide (6.12 g, 255 mmol) and the reactionmixture was stirred at rt for 16 hrs. On completion, the reactionmixture was poured into 3 L cool water and acidified with 1Nhydrochloric acid solution until pH=4-5. The aqueous phase was extractedwith ethyl acetate (3×2 L), dried over anhydrous sodium sulfate,filtrated and concentrated in vacuo to give the title compound. ¹H NMR(400 MHz, CDCl3) δ=7.59 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 5.37(d, J=6.3 Hz, 1H), 5.25 (d, J=6.8 Hz, 1H), 4.89 (d, J=6.3 Hz, 1H), 4.74(d, J=3.4 Hz, 1H), 4.72 (d, J=7.3 Hz, 1H), 3.83 (d, J=10.5 Hz, 1H), 3.67(s, 2H), 3.38-3.28 (m, 2H), 1.37 (s, 9H), 0.93-0.82 (m, 2H), 0.01 (s,9H).

Step 2—Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate

To a mixture of2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetic acid (38.0 g, 86.0 mmol) and potassium carbonate (23.7 g, 172mmol) in dimethylformamide (360 mL) was added 3-bromoprop-1-ene (20.8 g,172 mmol) in one portion and the reaction mixture was stirred at rt for16 hrs. On completion, the reaction mixture was poured in 3 L water andextracted with ethyl acetate (3×1 L). The combined organic layer wasdried over anhydrous sodium sulfate, filtrated and concentrated invacuo. The resulting oil was purified by silica gel chromatography(petroleum ether:ethyl acetate=10:1) to give the title compound. ¹H NMR(400 MHz, CDCl3) δ=7.60 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H),5.98-5.86 (m, 1H), 5.37 (d, J=6.3 Hz, 1H), 5.30 (dd, J=1.4, 17.2 Hz,1H), 5.27-5.21 (m, 2H), 4.89 (d, J=6.3 Hz, 1H), 4.76-4.68 (m, 2H), 4.61(d, J=5.6 Hz, 2H), 3.84 (d, J=10.5 Hz, 1H), 3.68 (s, 2H), 3.34 (t, J=8.2Hz, 2H), 1.36 (s, 9H), 0.92-0.84 (m, 2H), 0.01 (s, 9H).

Step 3—(±)-Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-methyl-propanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(500 mg, 1.04 mmol) in N,N-dimethylformamide (15 mL) was added LiHMDS (1M, 10.4 mL) dropwise at 0° C. After the reaction mixture was stirred for0.5 hr, a solution of methyl iodide (1.48 g, 10.4 mmol) inN,N-dimethylformamide (1 mL) was added dropwise and the reaction mixturewas stirred at rt for 6.5 hrs. On completion, the reaction mixture waspoured into 100 mL cool water and extracted with ethyl acetate (3×50mL). The combined layer was dried over anhydrous sodium sulfate,filtrated and concentrated in vacuo. The resulting product was purifiedby silica gel chromatography (petroleum ether:ethyl acetate=5:1) to givethe title compound (500 mg, 50% purity, 47% yield) as colorless oil.LCMS: (ES⁺) m/z (M+23)⁺=532.1, tR=1.122.

Step 4—Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-2-methylpropanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-methyl-propanoate (600 mg, 1.18 mmol) in ethanol (5 mL) wasadded hydrochloric acid/dioxane (4 M, 1.47 mL) and the reaction mixturewas stirred at 0° C. for 30 min. On completion, the reaction mixture wasbasified with saturated sodium bicarbonate solution until pH=8 andextracted with dichloromethane (3×30 mL). The combined layer was driedover anhydrous sodium sulfate, filtrated and concentrated in vacuo togive the title product (451 mg, 52.5% purity, 73% yield) as a lightyellow solid. LCMS: (ES⁺) m/z (M-NH2)⁺=259.0, tR=1.209.

Allyl 1-(4-(3-aminooxetan-3-yl)phenyl)cyclopropanecarboxylate(Intermediate BU)

Step 1—(±)-Allyl1-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)cyclopropanecarboxylate

To a mixture of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (200 mg, 415 umol, synthesized via Steps 1-2 ofIntermediate BT) in N,N-dimethylformamide (2.00 mL) was added thesolution of LiHMDS in hexane (1.66 mL, 1.66 mmol, 1M) dropwise at rt.Then, a solution of 1,2-dibromoethane (125 mg, 664 umol) inN,N-dimethylformamide (1.00 mL) was added at rt under nitrogenatmosphere. The resultant mixture was stirred at rt for 16 hrs. Oncompletion, to the mixture was added ammonium chloride solution (sat. 10mL) and the mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic phase was washed with brine (30 mL), dried over sodiumsulfate, and concentrated in vacuo to give a residue which was purifiedby column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) togive the title compound. ¹H NMR (400 MHz, CDCl₃-d) δ=7.56 (d, J=8.4 Hz,2H), 7.40 (d, J=8.4 Hz, 2H), 5.84-5.81 (m, 1H), 5.37 (d, J=6.4 Hz, 1H),5.24 (d, J=6.8 Hz, 1H), 5.19-5.13 (m, 2H), 4.89 (d, J=6.0 Hz, 1H),4.74-4.69 (m, 2H), 4.55 (d, J=5.2 Hz, 2H), 3.85 (d, J=10.4 Hz, 1H), 3.34(t, J=8.0 Hz, 2H), 1.65-1.62 (m, 2H), 1.35 (s, 9H), 1.22-1.19 (m, 2H),0.88 (t, J=8.8 Hz, 2H), 0.00 (s, 9H).

Step 2—Allyl 1-(4-(3-aminooxetan-3-yl)phenyl)cyclopropanecarboxylate

To a solution of (±)-allyl1-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl] cyclopropanecarboxylate (100 mg, 197 umol) inethanol (1.00 mL) was added hydrochloride/dioxane (4 M, 0.2 mL) dropwiseat 0° C. The resultant mixture was stirred at 0° C. for 2 hrs. Oncompletion, to the mixture was added sodium bicarbonate (sat. 10 mL) andthe mixture was extracted with dichloromethane (3×10 mL). The combinedorganic phase was washed with brine (30 mL), dried over sodium sulfate,and concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z(M-NH2)⁺=257.2, tR=0.609.

Allyl 2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate(Intermediate BV)

Step1—(±)-2-(3-Fluoro-4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)acetic acid

To a mixture of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]acetate(1.40 g, 2.87 mmol) in tetrahydrofuran (10.0 mL) and water (5.00 mL) wasadded lithium hydroxide (602 mg, 14.3 mmol) in one portion at 30° C.under nitrogen. The mixture was stirred at rt for 16 hrs. On completion,the mixture was concentrated in vacuo to remove tetrahydrofuran, and theaqueous phase was washed with ethyl acetate (10 mL) three times. To theaqueous phase was added 2 M hydrochloride acid to adjust pH=4-5. Theproduct was extracted with dichloromethane (20 mL) three times. Thecombined organic phase was washed with brine (50 mL) and concentrated invacuo to give the title compound. ¹H NMR (400 MHz, CDCl₃-d) δ=7.38 (t,J=8.0 Hz, 1H), 7.17-7.13 (m, 2H), 5.10 (d, J=7.2 Hz, 1H), 5.03 (d, J=7.2Hz, 1H), 4.98 (d, J=5.6 Hz, 2H), 4.44 (d, J=10.8 Hz, 1H), 4.01 (d,J=10.8 Hz, 1H), 3.63 (s, 2H), 3.63-3.25 (m, 2H), 1.19 (s, 9H), 0.81 (t,J=8 Hz, 2H), 0.00 (s, 9H).

Step 2—(±)-Allyl2-(3-fluoro-4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)acetate

To a solution of(±)-2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]aceticacid (1.20 g, 2.61 mmol) in N,N-dimethylformamide (10.0 mL) was addedpotassium carbonate (721 mg, 5.22 mmol) at rt. Then, 3-bromoprop-1-ene(632 mg, 5.22 mmol) was added dropwise under nitrogen atmosphere. Theresulting mixture was stirred at rt for 16 hrs. On completion, to themixture was added water (20 mL) and the mixture was extracted with ethylacetate (3×20 mL). The combined organic phase was washed with brine (60mL), dried over sodium sulfate, and concentrated in vacuo to give aresidue which was purified by column chromatography (petroleumether:ethyl acetate=15:1 to 10:1) to give the title compound. ¹H NMR(400 MHz, CDCl₃-d) δ=7.26 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H),7.05 (d, J=11.6 Hz, 1H), 5.95-5.89 (m, 1H), 5.29 (d, J=18.0 Hz, 1H),5.24-5.21 (m, 2H), 5.18 (d, J=7.2 Hz, 1H), 5.09 (d, J=7.2 Hz, 2H), 4.60(d, J=5.6 Hz, 2H), 4.55 (d, J=10.8 Hz, 1H), 4.15 (d, J=10.2 Hz, 1H),3.64 (s, 2H), 3.44-3.29 (m, 2H), 1.24 (s, 9H), 0.88 (t, J=7.2 Hz, 2H),0.00 (s, 9H).

Step 3—(±)-Allyl2-(3-fluoro-4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)-2-methylpropanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]acetate(250 mg, 500 umol) in N,N-dimethylformamide (3.00 mL) was added thesolution of LiHMDS in hexane (1 M, 5.00 mL) dropwise at 0° C. undernitrogen atmosphere. The mixture was stirred at 0° C. for 0.5 hrs, then,a solution of iodomethane (852 mg, 6.00 mmol) in N,N-dimethylformamide(0.5 mL) was added. The resultant mixture was stirred for 3 hrs at 0° C.On completion, to the mixture was added cooled ammonium chloridesolution (10 mL) and the mixture was extracted with ethyl acetate (3×10mL). The combined organic phase was washed with brine (20 mL), driedover sodium sulfate, and concentrated in vacuo to give a residue whichwas purified by column chromatography (petroleum ether:ethylacetate=10:1 to 5:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃-d) δ=7.28 (t, J=8.0 Hz, 1H), 7.18-7.16 (m, 1H), 7.12-7.06 (m, 1H),5.93-5.81 (m, 1H), 5.28-5.19 (m, 4H), 5.11 (d, J=7.2 Hz, 2H), 4.59-4.56(m, 3H), 4.15 (d, J=10.4 Hz, 1H), 3.44-3.34 (m, 2H), 1.60 (s, 6H), 1.27(s, 9H), 0.90 (t, J=6.8 Hz, 2H), 0.027 (s, 9H).

Step 4—Allyl2-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-2-methylpropanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-fluoro-phenyl]-2-methyl-propanoate(100 mg, 189 umol) in ethanol (1.00 mL) was added hydrochloride/dioxane(4 M, 154 uL) dropwise at 0° C. under nitrogen atmosphere. The mixturewas stirred at 0° C. for 1 hr. On completion, to the mixture was addedaqueous sodium bicarbonate (5 mL, sat.) and the mixture was extractedwith dichloromethane (3×5 mL). The combined organic phase was washedwith brine (15 mL), dried over sodium sulfate, and concentrated in vacuoto give the title compound. LCMS: (ES⁺) m/z (M-NH2)⁺=277.0, tR=0.586.

Ethyl 2-[4-(3-aminooxetan-3-yl)-3-chloro-phenyl]acetate (IntermediateBW)

To a mixture of (±)-ethyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-3-chloro-phenyl]acetate (250 mg, 495 umol, synthesized viaSteps 1-2 of BQ) in ethanol (2 mL) was added hydrochloric acid/dioxane(4 M, 124 uL) at 0° C. Then the mixture was stirred at 0° C. for 0.5hour. On completion, the mixture was dried with bubbling nitrogen. Thenthe residue was triturated with 20 mL methyl tert-butyl ether andfiltrated to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=270.2,tR=0.609.

2-[4-(3-Aminooxetan-3-yl)phenyl]acetonitrile (Intermediate BX)

Step 1—(±)-Ethyl4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]benzoate

To a solution of (±)-ethyl4-[3-(tert-butylsulfinylamino)oxetan-3-yl]benzoate (4.80 g, 14.7 mmol,synthesized via Steps 1-3 of Intermediate AE) in tetrahydrofuran (100mL) was added sodium hydride (885 mg, 22.1 mmol, 60% purity) at 0° C.,and the mixture was stirred at 0° C. for 0.5 hr. SEM-Cl (3.69 g, 22.1mmol) was added into the mixture and the resulting mixture was warmed tort and stirred at rt for 1 hr. On completion, the mixture was pouredinto ice water (150 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a residue. The residue was purifiedwith silica gel chromatograph (petroleum ether:ethyl acetate=10:1) toafford the title compound. ¹H NMR (400 MHz, CDCl3) δ=8.18-8.07 (m, 2H),7.77-7.69 (m, 2H), 5.41 (d, J=6.4 Hz, 1H), 5.29 (d, J=6.8 Hz, 1H), 4.91(d, J=6.4 Hz, 1H), 4.78-4.69 (m, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.86 (d,J=10.5 Hz, 1H), 3.38-3.32 (m, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.38 (s, 9H),0.93-0.84 (m, 2H), 0.04-0.01 (s, 9H)

Step2—(±)-N-[3-[4-(hydroxymethyl)phenyl]oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxy-methyl)propane-2-sulfinamide

To a solution of (±)-ethyl4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]benzoate (5.10 g, 11.1 mmol) in tetrahydrofuran (100 mL) was addedlithium aluminum hydride (849 mg, 22.3 mmol) at 0° C. under a nitrogenatmosphere. The mixture was stirred at 0° C. for 1 hr. On completion,water (0.5 mL) was added dropwise into the mixture followed by 15%sodium hydroxide solution (1.5 mL). After stirring for 0.5 hr, morewater (1.5 mL) was added into the mixture and the resulting mixture wasconcentrated in vacuo to give a residue. The residue was washed withwater (100 mL) and extracted with ethyl acetate (3×80 mL). The combinedorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified withsilica gel chromatograph (petroleum ether:ethyl acetate=1:1) to affordthe title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.65 (d, J=8.3 Hz, 2H),7.46 (d, J=8.3 Hz, 2H), 5.39 (d, J=6.3 Hz, 1H), 5.28 (d, J=6.8 Hz, 1H),4.93 (d, J=6.3 Hz, 1H), 4.80-4.68 (m, 4H), 3.86 (d, J=10.5 Hz, 1H), 3.36(t, J=8.3 Hz, 2H), 1.38 (s, 9H), 0.95-0.84 (m, 2H), 0.05-0.02 (s, 9H).

Step3—(±)-[4-[3-[Tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]methylmethanesulfonate and(±)-N-(3-(4-(chloromethyl)phenyl)oxetan-3-yl)-2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propane-2-sulfinamide

To a solution of(±)-N-[3-[4-(hydroxymethyl)phenyl]oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide (1.00 g, 2.42 mmol), triethylamine (489 mg,4.84 mmol) and DMAP (44.3 mg, 363 umol) in dichloromethane (30 mL) wasadded methanesulfonyl chloride (415 mg, 3.63 mmol) dropwise at 0° C. Theresulting mixture was allowed to warm to rt and stirred at rt for 16hrs. On completion, water (30 mL) was added into the reaction mixtureand the organic layer was separated. The organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound as a mixture of themesylate and the chloride. LCMS: (ES⁺) m/z (M+Na)⁺=454.2, tR=1.065.

Step4—(±)-N-[3-[4-(Cyanomethyl)phenyl]oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxy-methyl)propane-2-sulfinamide

To a solution of(±)-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]methylmethanesulfonate and(±)-N-(3-(4-(chloromethyl)phenyl)oxetan-3-yl)-2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propane-2-sulfinamide(900 mg) and sodium iodide (27.4 mg, 183 umol) in N,N-dimethylformamide(20 mL) was added sodium cyanide (134 mg, 2.75 mmol), and the resultingmixture was stirred at rt for 16 hrs. On completion, the mixture wasdiluted with water (200 mL) and the precipitate was filtered. The filtercake was dried in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=7.69 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.40 (d, J=6.4Hz, 1H), 5.28 (d, J=6.8 Hz, 1H), 4.88 (d, J=6.4 Hz, 1H), 4.74 (d, J=5.0Hz, 1H), 4.72 (s, 1H), 3.83 (d, J=10.5 Hz, 1H), 3.79 (s, 2H), 3.36 (t,J=8.5 Hz, 2H), 1.39 (s, 9H), 0.93-0.87 (m, 2H), 0.05-0.02 (s, 9H).

Step 5—2-[4-(3-Aminooxetan-3-yl)phenyl]acetonitrile

To a solution of(±)-N-[3-[4-(cyanomethyl)phenyl]oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide (250 mg, 591 umol) in ethanol (5 mL) wasadded hydrogen chloride/dioxane (2 mL) dropwise, and the resultingmixture was stirred at 0° C. for 0.5 hr. On completion, saturated sodiumbicarbonate solution (20 mL) was added into the mixture and the mixturewas extracted with ethyl acetate (2×30 mL). the combined organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give the title compound (120 mg, 84.5% purity, 92% yield) aswhite solid. LCMS: (ES⁺) m/z (M-NH₂)⁺=172.0, tR=0.480.

N-((4-(3-Aminooxetan-3-yl)phenyl)sulfonyl)acetamide (Intermediate BY)

Step 1—3-(4-Bromophenyl)oxetan-3-amine hydrochloride

To a mixture of(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(1.00 g, 3.01 mmol, synthesized via Steps 1-2 of Intermediate AE) inethanol (10.0 mL) was added hydrochloride/dioxane (4 M, 2.00 mL)dropwise at 0° C. The mixture was stirred at 0° C. for 2 hrs. Oncompletion, to the mixture was added 2-methoxy-2-methylpropane (30 mL)at 0° C. The mixture was filtered, and the solid was dried in vacuo togive the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=9.33 (br, s, 2H),7.71 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 5.00 (d, J=8.8 Hz, 2H),4.87 (d, J=8.4 Hz, 2H).

Step 2—Benzyl (3-(4-bromophenyl)oxetan-3-yl)carbamate

To a solution of 3-(4-bromophenyl)oxetan-3-amine hydrochloride (670 mg,2.53 mmol) in a mixture solvent of tetrahydrofuran (8.00 mL) and water(20.0 mL) was added sodium carbonate (804 mg, 7.59 mmol) in one portionat rt. Then, benzyl carbonochloridate (518 mg, 3.04 mmol) was added. Theresultant mixture was stirred for 16 hrs at rt. On completion, themixture was concentrated in vacuo to remove the tetrahydrofuran and theaqueous was extracted with ethyl acetate (3×20 mL). The combined organicphase was washed with brine (60 mL), dried over sodium sulfate, andconcentrated in vacuo to give a crude product which was purified bycolumn chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) togive the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=8.57 (br, s, 1H),7.59 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.38-7.31 (m, 5H), 5.01(s, 2H), 4.83 (d, J=6.4 Hz, 2H), 4.69 (d, J=6.4 Hz, 2H).

Step 3—Benzyl(3-(4-((triisopropylsilyl)thio)phenyl)oxetan-3-yl)carbamate

To a mixture of benzyl N-[3-(4-bromophenyl)oxetan-3-yl]carbamate (1.00g, 2.76 mmol), palladium acetate (31.0 mg, 138 umol), triphenylphosphine(159 mg, 607 umol), and cesium carbonate (1.35 g, 4.14 mmol) in toluene(20.0 mL) was added triisopropyl(sulfanyl)silane (789 mg, 4.14 mmol) inone portion at rt under nitrogen atmosphere. The mixture was heated to120° C. and stirred for 16 hrs. On completion, the mixture wasconcentrated in vacuo to remove the toluene. The residue was dilutedwith water (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic phase was dried over sodium sulfate and concentrated invacuo to give a residue which was purified by column chromatography(petroleum ether:ethyl acetate=10:1 to 5:1) to give the title compound.¹H NMR (300 MHz, CDCl₃-d) δ=7.42 (d, J=8.1 Hz, 2H), 7.27-7.25 (m, 7H),5.44 (s, 1H), 5.01 (s, 2H), 4.91 (s, 2H), 4.78 (s, 2H), 1.23-1.11 (m,3H), 1.01 (d, J=6.9 Hz, 18H).

Step 4—Benzyl (3-(4-(chlorosulfonyl)phenyl)oxetan-3-yl)carbamate

To a mixture of benzylN-[3-(4-triisopropylsilylsulfanylphenyl)oxetan-3-yl]carbamate (1.00 g,2.12 mmol) in acetic acid (6.40 mL) and water (2.10 mL) was added NCS(1.16 g, 8.69 mmol) at rt and then stirred for 1 hr. On completion, tothe mixture was added water (30 mL) and the mixture was extracted withethyl acetate (3×10 mL). The combined organic phase was washed withbrine (30 mL), dried over sodium sulfate, and concentrated in vacuo togive a crude product which was purified by column chromatography(petroleum ether:ethyl acetate=4:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=382.0. tR=0.846

Step 5—Benzyl (3-(4-(chlorosulfonyl)phenyl)oxetan-3-yl)carbamate

To a solution of benzylN-[3-(4-chlorosulfonylphenyl)oxetan-3-yl]carbamate (800 mg, 2.10 mmol)in tetrahydrofuran (5.00 mL) was added a solution of ammonia (gas) intetrahydrofuran (4M, 10 mL) dropwise at rt. The mixture was stirred atrt for 0.5 hrs. On completion, the mixture was concentrated in vacuo togive the title compound. ¹H NMR (300 MHz, DMSO-d6) δ=8.69 (s, 1H), 7.85(d, J=8.1 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.37-7.25 (m, 7H), 5.02 (s,2H), 4.85 (d, J=6.6 Hz, 2H), 4.73 (d, J=6.3 Hz, 2H).

Step 6—Benzyl (3-(4-(N-acetylsulfamoyl)phenyl)oxetan-3-yl)carbamate

To a mixture of EDCI (874 mg, 4.56 mmol), N,N-dimethylpyridine (557 mg,4.56 mmol), and acetic acid (256 mg, 4.26 mmol) in N,N-dimethylformamide(5.50 mL) was added benzyl N-[3-(4-sulfamoylphenyl)oxetan-3-yl]carbamate(550 mg, 1.52 mmol) portion-wise at rt. The mixture was stirred at rtfor 2 hrs. On completion, to the mixture was added brine (15 mL) and themixture was extracted with ethyl acetate (3×15 mL). The aqueous phasewas concentrated in vacuo to give a residue which was purified by columnchromatography (petroleum ether:ethyl acetate=5:1 to 1:1 todichloromethane:methanol=10:1) to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ=8.66 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz,2H), 7.38 (m, 5H), 5.02 (s, 2H), 4.86-4.82 (m, 2H), 4.75-4.73 (m, 2H),2.57 (s, 3H).

Step 7—N-((4-(3-Aminooxetan-3-yl)phenyl)sulfonyl)acetamide

To a mixture of benzylN-[3-[4-(acetylsulfamoyl)phenyl]oxetan-3-yl]carbamate (300 mg, 742 umol)in methanol (1.00 mL) was added palladium/carbon (100 mg, 10% w/w) at rtunder hydrogen gas (50 psi). The mixture was stirred at rt for 2 hrs. Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give the title compound. LCMS: (ES⁺) m/z (M-NH2)⁺=254.2.tR=0.208.

(±) Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)butanoate (Intermediate BZ)

Step 1—(1) Allyl2-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)butanoate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-phenyl]acetate(1.20 g, 2.49 mmol, synthesized via Steps 1-2 of Intermediate BT) inanhydrous tetrahydrofuran (20 mL) was added LiHMDS (1 M, 2.99 mL) at 0°C. for 0.5 hr. Then, iodoethane (388 mg, 2.49 mmol) was added at 0° C.The reaction mixture was warmed to rt and stirred for 0.5 hrs. Oncompletion, the reaction mixture was quenched with saturated ammoniumchloride (10 mL), extracted with ethyl acetate (3×50 mL), and washedwith brine (20 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated in vacuo to give red oil. The red oil waspurified by silica gel chromatography (petroleum ether:ethylacetate=20:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.58(d, J=7.4 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.89 (tdd, J=16.8, 11.0, 5.6Hz, 1H), 5.37 (d, J=6.0 Hz, 1H), 5.30-5.17 (m, 3H), 4.92-4.86 (m, 1H),4.77-4.67 (m, 2H), 4.65-4.52 (m, 2H), 3.85 (d, J=10.6 Hz, 1H), 3.52 (t,J=7.8 Hz, 1H), 3.34 (t, J=8.2 Hz, 2H), 2.13 (td, J=14.2, 7.2 Hz, 1H),1.82 (td, J=14.0, 7.2 Hz, 1H), 1.36 (s, 9H), 0.96-0.84 (m, 5H), −0.04(s, 9H).

Step 2—(±) Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)butanoate

To a solution of (I) allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-phenyl]butanoate(3.20 g, 6.28 mmol) in ethanol (30 mL) was added HCl/dioxane (4 M, 3.92mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. Oncompletion, the reaction mixture was quenched with aqueous saturatedsodium bicarbonate (20 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound. LCMS: (ES⁺) m/z (M-NH₂)⁺=259.2, tR=0.639.

(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-2-cyclobutyl-acetate(Intermediate CA)

Step 1—(±)-Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-cyclobutyl-acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(2.00 g, 4.15 mmol, synthesized via Steps 1-2 of Intermediate BT) inN,N-dimethylformamide (40 mL) was added LiHMDS (1 M, 6.23 mL) dropwiseat 0° C. and the reaction mixture was stirred for 1.5 hrs. Then sodiumiodide (124 mg, 830 umol) and bromocyclobutane (2.80 g, 20.7 mmol) wasadded in turn and the reaction mixture was stirred at rt for 1.5 hrs. Oncompletion, the reaction mixture was poured into 100 mL cool water,acidified with citric acid solution until pH=6 and extracted with ethylacetate (3×100 mL). The combined layer was dried over anhydrous sodiumsulfate, filtrated and concentrated in vacuo. The resulting oil waspurified by silica gel chromatography (petroleum ether:ethylacetate=7:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.56(d, J=7.9 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 5.94-5.81 (m, 1H), 5.36 (dd,J=0.9, 6.2 Hz, 1H), 5.29-5.14 (m, 3H), 4.88 (dd, J=2.6, 6.2 Hz, 1H),4.73 (d, J=7.0 Hz, 1H), 4.70 (dd, J=3.9, 10.7 Hz, 1H), 4.64-4.47 (m,2H), 3.85 (dd, J=2.4, 10.5 Hz, 1H), 3.61 (d, J=10.9 Hz, 1H), 3.34 (t,J=8.2 Hz, 2H), 3.05-2.92 (m, 1H), 2.26-2.13 (m, 1H), 1.95-1.77 (m, 4H),1.62 (br. s., 1H), 1.35 (s, 9H), 0.88 (dd, J=6.8, 9.0 Hz, 2H), 0.01 (s,9H).

Step 2—(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-2-cyclobutyl-acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-cyclobutyl-acetate(1.40 g, 2.61 mmol) in ethanol (10 mL) was added hydrochloric acid/ethylacetate (4 M, 13 mL) and the reaction mixture was stirred at 0° C. for0.5 hr. On completion, the reaction mixture was basified with saturatedsodium bicarbonate (5 mL) until pH=8 and extracted with dichloromethane(3×10 mL). The combined layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The resulting oil was purified bysilica gel chromatography (petroleum ether:ethyl acetate=0:1) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=302.0, tR=0.916.

(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-3-methyl-butanoate(Intermediate

Step 1—(±)-Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(3.50 g, 7.27 mmol, synthesized via Steps 1-2 of Intermediate BT) intetrahydrofuran (10 mL) was added LiHMDS (1 M, 9.45 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 30 min. 2-iodopropane (1.61 g,9.45 mmol) was added to the reaction mixture and the mixture was stirredat rt for 3 hrs. On completion, the mixture was quenched with ammoniumchloride solution (20 mL), extracted with ethyl acetate (2×30 mL), driedand concentrated. The residue was purified by column chromatography(petroleum ether:ethyl acetate=5:1) to give the title compound. LCMS:(ES⁺) m/z (M+23)⁺=546.4, tR=1.072.

Step 2—(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-3-methyl-butanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoate (2.50 g, 4.77 mmol) in ethanol (20 mL) wasadded hydrogen chloride/dioxane (4 M, 14 mL) at 0° C. The reactionmixture was stirred at 0° C. for 3 hrs. On completion, the reactionmixture was concentrated in vacuo to give the title compound. LCMS:(ES⁺) m/z (M-NH₂)⁺=273.3, tR=0.673.

(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-2-cyclopentyl-acetate(Intermediate CC)

Step 1—(±)-Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-acetate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(2.20 g, 4.57 mmol, synthesized via Steps 1-2 of Intermediate BT) inN,N-dimethylformamide (20 mL) was added LiHMDS (1 M, 13.7 mL) at 0° C.The reaction mixture was stirred at 0° C. for 30 min. Bromocyclopentane(2.04 g, 13.7 mmol) was added to the reaction mixture and the mixturewas stirred at 50° C. for 3 hrs. On completion, the mixture was quenchedwith ammonium chloride solution (80 mL) and extracted with ethyl acetate(2×100 mL). The combined organic layer was washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give a residue. The residue was dried in vacuo to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=7.60-7.54 (m, 2H), 7.43 (d, J=8.4Hz, 2H), 5.96-5.84 (m, 1H), 5.38 (dd, J=2.8, 6.2 Hz, 1H), 5.31-5.24 (m,2H), 5.22 (dd, J=1.1, 10.4 Hz, 1H), 4.93-4.88 (m, 1H), 4.79-4.68 (m,2H), 4.67-4.59 (m, 1H), 4.58-4.49 (m, 1H), 3.87 (dd, J=2.6, 10.5 Hz,1H), 3.38 (d, J=3.5 Hz, 1H), 3.37-3.32 (m, J=6.7 Hz, 2H), 2.68-2.49 (m,1H), 2.00-1.83 (m, 1H), 1.76-1.62 (m, 2H), 1.59-1.40 (m, 3H), 1.37 (s,9H), 1.34-1.26 (m, 1H), 1.10-0.96 (m, 1H), 0.94-0.87 (m, 2H), 0.00 (s,9H).

Step 2—(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-2-cyclopentyl-acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-acetate (3.20 g, 5.85 mmol) in ethanol (20 mL) wasadded hydrogen chloride/dioxane (4 M, 8 mL) at 0° C. The reactionmixture was stirred at 0° C. for 2 hrs. On completion, the reactionmixture was neutralized with saturated sodium bicarbonate solution topH=8, and extracted with dichloromethane (2×30 mL). The combined organiclayer was concentrated in vacuo to give the title compound. LCMS: (ES⁺)m/z (M-NH₂)⁺=299.1, tR=0.958.

(±)-Allyl 5-acetoxy-2-[4-(3-aminooxetan-3-yl)phenyl]pentanoate(Intermediate CD)

Step 1—3-bromopropyl acetate

To a solution of 3-bromopropan-1-ol (5.00 g, 35.97 mmol) in anhydrousdichloromethane 30 mL was added triethylamine (7.28 g, 71.9 mmol). Then,the mixture was cooled to 0° C. and acetyl chloride (4.24 g, 53.9 mmol)was added dropwise over 10 mins. Finally, the mixture was warmed to rtand stirred for 20 mins. On completion, the reaction mixture wasquenched by addition of ice water 30 mL, and the resulting mixture wasextracted with dichloromethane (2×30 mL). The combined organic layerswere washed with saturated sodium bicarbonate solution 30 mL, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give aresidue. The residue was purified by distillation, collecting thefraction within 40-45° C. under reduced pressure with an oil pump togive the title compound. ¹H NMR (400 MHz, CD₃Cl) δ=4.21 (t, J=6.1 Hz,2H), 3.47 (t, J=6.6 Hz, 2H), 2.18 (quin, J=6.3 Hz, 2H), 2.06 (s, 3H).

Step 2—(±)-Allyl5-acetoxy-2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)-amino]oxetan-3-yl]phenyl]pentanoate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (400 mg, 830 umol, synthesized via Steps 1-2 ofIntermediate BT) in anhydrous N, N-dimethylformamide (10 mL) was addedLiHMDS (1 M, 1.08 mL) dropwise at 0° C. The mixture was stirred at 0° C.for 30 min then 3-bromopropyl acetate (157 mg, 871 umol) in anhydrous N,N-dimethylformamide (5 mL) was added dropwise. Afterwards, the mixturewas warmed to rt and stirred at rt for 2.5 hrs. On completion, thereaction mixture was poured into 10 mL ice saturated ammonium chloridesolution, and extracted with ethyl acetate (3×10 mL). The organic phasewas collected, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by column chromatography (petroleumether:ethyl acetate=10:1 to 5:1) to give the title compound. ¹H NMR (400MHz, CD₃Cl) δ=7.58 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 5.93-5.78(m, 1H), 5.37 (d, J=6.3 Hz, 1H), 5.27-5.17 (m, 3H), 4.86 (d, J=5.4 Hz,1H), 4.75-4.67 (m, 2H), 4.64-4.50 (m, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.83(dd, J=1.1, 10.6 Hz, 1H), 3.61 (t, J=7.7 Hz, 1H), 3.34 (t, J=8.2 Hz,2H), 2.21-2.09 (m, 1H), 2.04 (s, 3H), 1.92-1.80 (m, 1H), 1.67-1.60 (m,2H), 1.35 (s, 9H), 0.88 (dd, J=6.9, 8.9 Hz, 2H), 0.00 (s, 9H).

Step 3—(±)-Allyl 5-acetoxy-2-[4-(3-aminooxetan-3-yl)phenyl]pentanoate

(±)-Allyl5-acetoxy-2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]pentanoate (260 mg, 446 umol) was dissolved in formic acid (1mL). The mixture was stirred at rt for 2 hrs. On completion, thereaction mixture was alkalified with saturated sodium bicarbonatesolution (20 mL) until the pH>7. The mixture was extracted withdichloromethane (2×15 mL), and the organic phase was collected, driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=348.3, tR=0.818.

(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)pentanoate (Intermediate CE)

Step 1—(±)-Allyl2-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfin-amido)oxetan-3-yl)phenyl)pentanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (322 mg, 668 umol, synthesized via Steps 1-2 ofIntermediate BT) in anhydrous tetrahydrofuran (2 mL) was added lithiumdiisopropylamide (2 M, 500 uL) at 0° C. for 0.5 hr. Then, 1-iodopropane(170 mg, 1.00 mmol) was added at 0° C. The reaction mixture was warmedto rt and stirred for 12 hrs. On completion, the reaction mixture wasquenched with saturated ammonium chloride (1 mL), extracted with ethylacetate (3×5 mL), and washed with brine (5 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ=7.57(d, J=6.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.89 (tdd, J=16.8, 10.9, 5.6Hz, 1H), 5.37 (dd, J=6.2, 2.0 Hz, 1H), 5.25 (dd, J=12.0, 5.4 Hz, 2H),5.20 (d, J=10.6 Hz, 1H), 4.89 (dd, J=6.0, 3.0 Hz, 1H), 4.77-4.68 (m,2H), 4.65-4.51 (m, 2H), 3.85 (dd, J=10.6, 1.6 Hz, 1H), 3.62 (t, J=7.8Hz, 1H), 3.34 (t, J=8.2 Hz, 2H), 2.08 (dt, J=14.2, 8.4 Hz, 1H), 1.77(dd, J=15.4, 6.8, Hz, 1H), 1.36 (s, 9H), 1.31-1.25 (m, 2H), 0.96-0.91(m, 3H), 0.90-0.85 (m, J=9.0 Hz, 2H), 0.01 (s, 9H)

Step 2—(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)pentanoate

To a solution of(±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-phenyl]pentanoate(150 mg, 286 umol) in ethanol (2 mL) was added HCl/dioxane (4 M, 179 uL)at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. Oncompletion, the reaction mixture was quenched with aqueous saturatedsodium bicarbonate (2 mL) and extracted with ethyl acetate (3×5 mL). Thecombined organic phase was washed with saturated brine (5 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive the title compound. LCMS: (ES⁺) m/z (M-NH2)⁺=273.2, tR=0.674.

(±)-Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)-3-methylbutanoate(Intermediate CF)

Step 1—(±)-Ethyl2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)-3-methylbutanoate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (800 mg, 3.09 mmol,synthesized via Steps 1-2 of Intermediate AW) in N,N-dimethylformamide(5 mL) was added LiHMDS (1 M, 5.56 mL) dropwise at 0° C. under nitrogenand the reaction mixture was stirred for 0.5 hr at 0° C. Then2-iodopropane (577 mg, 3.40 mmol) was added and the reaction mixture wasstirred at rt for 2.5 hr. On completion, the reaction mixture was pouredinto 100 mL cool water and extracted with dichloromethane (3×30 mL). Thecombined layer was dried over anhydrous sodium sulfate, filtrated andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=20:1-5:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+1)⁺=302.2, tR=0.859.

Step 2—(±)-Ethyl2-(4-(3-carbamoyltetrahydrofuran-3-yl)phenyl)-3-methylbutanoate

To a solution of (±)ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-3-methyl-butanoate (430 mg,1.43 mmol) and potassium carbonate (79.0 mg, 572 umol) in dimethylsulfoxide (10 mL) was added hydrogen peroxide (1.30 g, 11.4 mmol, 30%solution). The mixture was stirred at rt for 2 hrs. On completion,sodium sulfite solution was added to the reaction mixture and themixture was extracted with ethyl acetate (3×20 mL). The organic layerwas washed with water (20 mL) and brine (10 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give the title product. LCMS: (ES⁺) m/z (M+H)⁺=320.3,tR=0.799.

Step 3—(±)-Ethyl2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)-3-methylbutanoate

To a mixture of ethyl(±)-2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-3-methyl-butanoate(420 mg, 1.31 mmol) in acetonitrile (8 mL) and water (8 mL) was addedPhI(CF₃CO₂)₂ (619 mg, 1.44 mmol) in one portion, and the mixture wasstirred at rt for 16 hrs. On completion, the mixture was concentrated invacuo. 1N hydrochloric acid (5 mL) was added into the mixture and themixture was washed with ethyl acetate (20 mL). The aqueous layer wasthen basified with sodium bicarbonate to pH=9 and extracted withdichloromethane (2×20 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound. LCMS: (ES⁺) m/z (2M+H)⁺=583.5, tR=0.709.

(±) Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)pentanoate(Intermediate

Step 1—(±) Ethyl 2-(4-(3-cyanotetrahydrofuran-3-yl)phenyl)pentanoate

To a solution of (±) ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (100 mg, 386 umol,synthesized via Steps 1-2 of Intermediate AW) in anhydrousN,N-dimethylformamide (2 mL) was added LiHMDS (1 M, 578.47 uL) at 0° C.for 0.5 hr. Then, 1-iodopropane (72.1 mg, 424 umol) was added at 0° C.The reaction mixture was warmed to rt and stirred for 1 hr. Oncompletion, the reaction mixture was quenched with saturated ammoniumchloride (1 mL), extracted with ethyl acetate (3×5 mL), and washed withbrine (5 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give red oil. The red oil waspurified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.42(d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.36 (d, J=9.0 Hz, 1H),4.21-4.11 (m, 4H), 4.03 (d, J=9.0 Hz, 1H), 3.56 (t, J=7.8 Hz, 1H),2.83-2.74 (m, 1H), 2.46 (td, J=13, 8.2 Hz, 1H), 2.11-1.99 (m, 1H),1.80-1.69 (m, 1H), 1.34-1.25 (m, 2H), 1.23 (t, J=7.0 Hz, 3H), 0.92 (t,J=7.2 Hz, 3H).

Step 2—(±) ethyl 2-(4-(3-carbamoyltetrahydrofuran-3-yl)phenyl)pentanoate

To a mixture of (±) ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]pentanoate (110 mg, 365 umol)and potassium carbonate (20.2 mg, 146 umol) in DMSO (1.50 mL) was addedhydrogen peroxide (157 mg, 1.39 mmol, 133 uL, 30% solution) in oneportion at rt. Then the mixture was heated to 60° C. (oil-bathtemperature) and stirred for 3 hours. On completion, the reactionmixture was diluted with water (2 mL), filtered and dried in vacuo togive the title compound. The white solid was used for the next stepdirectly without purification. LCMS: (ES⁺) m/z (M+1)⁺=320.1, tR=0.732.

Step 3—(±) Ethyl 2-(4-(3-aminotetrahydrofuran-3-yl)phenyl)pentanoate

To a solution of (±) ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]pentanoate (110 mg, 258umol) in acetonitrile (2 mL) and water (2 mL) was added PhI(OAc)₂ (100mg, 310 umol) at rt. The reaction mixture was stirred at rt for 3 hrs.On completion, the reaction mixture was quenched with saturated sodiumhypochlorite (5 mL). The reaction mixture was concentrated in vacuo. Theresidue was acidified with hydrochloric acid (2N, 5 mL) to pH=2 and theaqueous layer was washed with ethyl acetate (10 mL). Then to the aqueouslayer was added saturated sodium bicarbonate aqueous to pH=9, andextracted with ethyl acetate (3×20 mL). The combined organic layer waswashed with brine (10 mL) and dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound. LCMS:(ES⁺) m/z (M-NH₂)=275.3, tR=0.718.

(±)-Ethyl 2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate(Intermediate CH)

Step 1—(±)-Ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (1.35 g, 5.21 mmol) inN,N-dimethylformamide (10 mL) was added LiHMDS (10.4 mL 10.4 mmol)dropwise at 0° C. under nitrogen, and the reaction was stirred at 0° C.for 0.5 hr. Then sodium iodide (156 mg, 1.04 mmol) and bromocyclobutane(3.52 g, 26.1 mmol) were added into the solution in one portion at 0°C., and the reaction was stirred at rt for 2 hrs. On completion, 20 mLwater was added into the solution dropwise and the reaction wasextracted with the EtOAc (3×50 mL), washed with water (3×50 mL), driedover anhydrous sodium sulfate, and concentrated in vacuo to give thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ=7.36-7.31 (m, 2H), 7.28-7.23(m, 2H), 4.28 (d, J=9.0 Hz, 1H), 4.13-4.04 (m, 3H), 4.04-3.98 (m, 1H),3.95 (dd, J=0.9, 9.0 Hz, 1H), 3.47 (d, J=10.9 Hz, 1H), 2.95-2.82 (m,1H), 2.77-2.64 (m, 1H), 2.38 (td, J=8.2, 12.9 Hz, 1H), 2.17-2.04 (m,1H), 1.85-1.68 (m, 4H), 1.52-1.45 (m, 1H), 1.19-1.10 (m, 3H).

Step 2—(±)-Ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate (200 mg,638 umol) in dimethyl sulfoxide (5 mL) was added potassium carbonate(35.3 mg, 255 umol) and hydrogen peroxide (723 mg, 6.38 mmol) in oneportion at rt, and the reaction was stirred at rt for 1 hr. Oncompletion, the residue was poured into aqueous sodium sulfite (50 mL).The aqueous phase was extracted with ethyl acetate (3×20 mL). Thecombined organic phase was washed with brine (3×20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound.

Step 3—(±)-Ethyl2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate

To a solution of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-2-cyclobutyl-acetate (150mg, 453 umol) in acetonitrile (5 mL) and water (5 mL) was added[phenyl-(2,2,2-trifluoroacetyl)oxy-iodanyl]2,2,2-trifluoroacetate (234mg, 543 umol) in one portion at rt, and the reaction was stirred at rtfor 12 hrs. On completion, the aqueous phase was extracted with ethylacetate (3×20 mL). The combined organic phase was washed with brine(3×20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(dichloromethane:methanol=100:1-10:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=304.1, tR=0.789.

(±)-Ethyl2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate(Intermediate CI)

Step 1—(±)-Ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate

To a solution of (±)-ethyl2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]acetate (1.00 g, 3.86 mmol) indimethyl formamide (30 mL) was added lithium bis(trimethylsilyl)amide (1M, 3.86 mmol) at rt. The mixture was stirred at rt for 1 hr, thenbromocyclopentane (862 mg, 5.79 mmol) was added and the mixture wasstirred at 50° C. for 1 hr. On completion, the mixture was diluted withsaturated ammonium chloride (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 5:1)to give the title compound. LCMS: (ES⁺) m:z (M+H)⁺=328.3.

Step 2—(±)-Ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate

To a solution of ethyl(±)-2-[4-(3-cyanotetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate(1.00 g, 3.05 mmol) in dimethyl sulfoxide (10 mL) was added potassiumcarbonate (844 mg, 6.11 mmol) and hydrogen peroxide (2.59 g, 30.5 mmol,30% solution) at rt, and the mixture was stirred at rt for 7 hrs. Oncompletion, the mixture was diluted with water (10 mL) and extractedwith dichloromethane (3×20 mL). The organic layer was washed with water(3×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.38(d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 5.42 (br. s., 2H), 4.46 (d,J=8.8 Hz, 1H), 4.21-4.14 (m, 1H), 4.12-4.04 (m, 3H), 3.97 (q, J=7.3 Hz,1H), 3.28 (d, J=11.0 Hz, 1H), 2.89-2.79 (m, 1H), 2.55 (m, 1H), 2.39-2.31(m, 1H), 1.97-1.85 (m, 1H), 1.74-1.65 (m, 1H), 1.53-1.38 (m, 2H), 1.25(t, J=7.0 Hz, 3H), 1.04-0.94 (m, 1H).

Step 3—(±)-Ethyl2-[4-(3-aminotetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate

To a solution of (±)-ethyl2-[4-(3-carbamoyltetrahydrofuran-3-yl)phenyl]-2-cyclopentyl-acetate(60.0 mg, 173 umol) in acetonitrile (10 mL) and water (5 mL) was added[bis(trifluoroacetoxy)iodo]benzene (298 mg, 694 umol) and the mixturewas stirred at rt for 12 hrs. On completion, the mixture adjusted to pH7-9 with sodium bicarbonate. The mixture was then extracted withdichloromethane (2×20 mL), washed with brine (3×10 mL), and the organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto give the title compound. LCMS: (ES⁺) m:z (M-NH2)⁺=301.1.

(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-2-cyclohexylacetate(Intermediate CJ)

Step 1—(±)-Allyl2-cyclohexyl-2-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (200 mg, 415 umol, synthesized via Steps 1-2 ofIntermediate BT) in N,N-dimethylformamide (5 mL) was added LiHMDS (1 M,1.25 mL) dropwise at 0° C. After the reaction mixture was stirred for0.5 hr, iodocyclohexane (436 mg, 2.08 mmol) was added and the reactionmixture was stirred at rt for 2 hrs. On completion, the reaction mixturewas poured into 30 mL cool water and extracted with dichloromethane(3×30 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The resulting product waspurified by silica gel chromatography (petroleum ether:ethylacetate=20:1-10:1) to give the title compound. LCMS: (ES⁺) m/z(M+23)⁺=586.4, tR=1.229.

Step 2—(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-2-cyclohexylacetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-cyclohexyl-acetate (190 mg, 336 umol) in ethanol (10 mL) wasadded hydrochloric acid/dioxane (4 M, 421 uL) and the reaction mixturewas stirred at 0° C. for 45 min. On completion, the reaction mixture wasbasified with saturated sodium bicarbonate solution until pH=8 andextracted with dichloromethane (3×20 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound. LCMS: (ES⁺) m/z (2M+H)⁺=659.5,(M-NH₂)⁺=313.3, tR=0.789.

(±)-Allyl2-(4-(3-aminooxetan-3-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate(Intermediate CK)

Step 1—(±)-Allyl2-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(200 mg, 415 umol, synthesized via Steps 1-2 of Intermediate BT) inN,N-dimethylformamide (5 mL) was added LiHMDS (1 M, 1.25 mL) dropwise at0° C. After the reaction mixture was stirred for 1 hr, a solution of4-iodotetrahydropyran (440 mg, 2.08 mmol) in N,N-dimethylformamide (1mL) was added dropwise and the reaction mixture was stirred at rt for6.5 hrs. On completion, the reaction mixture was poured into 100 mL coolwater and extracted with ethyl acetate (3×30 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The resulting product was purified by silica gelchromatography (petroleum ether:ethyl acetate=20:1-10:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+23)⁺=588.4, tR=1.071.

Step 2—(±)-Allyl2-(4-(3-aminooxetan-3-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-tetrahydropyran-4-yl-acetate (230 mg, 406 umol) in ethanol (10mL) was added hydrochloric acid/dioxane (4 M, 508 uL) and the reactionmixture was stirred at 0° C. for 45 min. On completion, the reactionmixture was basified with saturated sodium bicarbonate solution untilpH=8 and extracted with dichloromethane (3×20 mL). The combined layerwas dried over anhydrous sodium sulfate, filtrated and concentrated invacuo to give the title compound. LCMS: (ES⁺) m/z (2M+H)⁺=663.4,tR=0.676.

Allyl 4-iodopiperidine-1-carboxylate (Intermediate CL)

Step 1—allyl 4-hydroxypiperidine-1-carboxylate

Piperidin-4-ol (CAS #5382-16-1, 6.99 g, 69.14 mmol) was dissolved in DCM(250 mL) with stirring. TEA (10.5 g, 103.71 mmol) was added, and thesolution was cooled to 0° C. Allyl carbonochloridate (CAS #2937-50-0,10.0 g, 82.9 mmol) was added dropwise via addition funnel over 30 min.The reaction was stirred at 20° C. for 18 hr. On completion, thereaction mixture was quenched with 1N HCl and extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(DCM/MeOH=100/1 to 10/1) to give the title compound. ¹H NMR (400 MHz,CDCl3) δ=5.96 (tdd, J=5.4, 10.6, 17.3 Hz, 1H), 5.36-5.28 (m, 1H), 5.23(qd, J=1.4, 10.5 Hz, 1H), 4.61 (td, J=1.5, 5.5 Hz, 2H), 3.90 (tdd,J=4.3, 8.4, 12.6 Hz, 3H), 3.16 (ddd, J=3.0, 9.8, 13.2 Hz, 2H), 1.90 (td,J=4.0, 8.5 Hz, 2H), 1.59 (d, J=3.9 Hz, 1H), 1.57-1.38 (m, 2H)

Step 2—allyl 4-iodopiperidine-1-carboxylate

To a solution of allyl 4-hydroxypiperidine-1-carboxylate (6.00 g, 32.4mmol) in DCM (150 mL) were added PPh₃ (11.05 g, 42.11 mmol) andimidazole (3.31 g, 48.59 mmol). The resulting solution was cooled to 0°C. and I₂ (9.87 g, 38.87 mmol) was added portion-wise. The mixture wasstirred at 20° C. for 18 hr. On completion, the reaction mixture waspoured into water and extracted with Et₂O. The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(PE/EtOAc=100:0 to 95:5 to 92:8) to give the title compound. ¹HNMR (400MHz, CDCl3) 6=6.03-5.88 (m, 1H), 5.36-5.18 (m, 2H), 4.61 (td, J=1.2, 5.6Hz, 2H), 4.48 (quin, J=5.8 Hz, 1H), 3.66 (td, J=5.2, 13.6 Hz, 2H), 3.40(td, J=5.7, 13.6 Hz, 2H), 2.06 (q, J=5.6 Hz, 4H).

(±)-Allyl4-[2-allyloxy-1-[4-(3-aminooxetan-3-yl)phenyl]-2-oxo-ethyl]piperidine-1-carboxylate(Intermediate CM)

Step 1—(±)-allyl4-[2-allyloxy-1-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-oxo-ethyl]piperidine-1-carboxylate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(1.50 g, 3.11 mmol, synthesized via Steps 1-2 of Intermediate BT) in THF(12 mL) was added LiHMDS (1 M, 4.67 mL) dropwise at 0° C. The mixturewas stirred at 0° C. for 30 min, then allyl4-iodopiperidine-1-carboxylate (2.75 g, 9.33 mmol) in THE (3 mL) wasadded dropwise. Then the mixture was warmed to rt and stirred at rt for15.5 hrs. On completion, the reaction mixture was poured into 50 mL icedsaturated ammonium chloride solution, and extracted with ethyl acetate(60 mL×3). The organic phase was collected, dried over anhydrous sodiumsulfate, and concentrated in vacuo to get a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=10:1 to 5:1) to give the title compound. 1H NMR (400 MHz, CDCl₃)δ=7.60 (dd, J=6.2, 8.1 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 6.02-5.80 (m,2H), 5.39 (t, J=7.0 Hz, 1H), 5.33-5.16 (m, 5H), 4.87 (dd, J=6.2, 10.1Hz, 1H), 4.77-4.48 (m, 6H), 4.27-3.99 (m, 2H), 3.84 (dd, J=4.5, 10.5 Hz,1H), 3.45-3.23 (m, 3H), 2.90-2.60 (m, 2H), 2.34-2.13 (m, 1H), 1.82 (d,J=12.5 Hz, 1H), 1.37 (s, 9H), 1.33-1.24 (m, 2H), 1.06-0.94 (m, 1H), 0.90(dd, J=7.0, 9.0 Hz, 2H), 0.02 (s, 9H).

Step 2—(±)-allyl4-[2-allyloxy-1-[4-(3-aminooxetan-3-yl)phenyl]-2-oxo-ethyl]piperidine-1-carboxylate

To a solution of allyl4-[2-allyloxy-1-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-2-oxo-ethyl]piperidine-1-carboxylate (1.10 g,1.70 mmol) in EtOH (10.0 mL) was added HCl/dioxane (4 M, 5.00 mL). Thereaction mixture was stirred at 0° C. for 2 hr. On completion, thereaction mixture was neutralized with saturated sodium bicarbonatesolution until pH=8, and extracted with dichloromethane (2×70 mL). Thecombined organic layer was concentrated in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=415.2, tR=0.690.

(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-4-methylpentanoate(Intermediate CN)

Step 1—(±)-Allyl4-methyl-2-(4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)phenyl)pentanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(500 mg, 1.04 mmol, synthesized via Steps 1-2 of Intermediate BT) inN,N-dimethylformamide (10 mL) was added LiHMDS (1 M, 1.87 mL) dropwiseat 0° C. After the reaction mixture was stirred for 0.5 hr,1-iodo-2-methyl-propane (210 mg, 1.14 mmol) was added dropwise and thereaction mixture was stirred at rt for 6.5 hrs. On completion, thereaction mixture was poured into 30 mL cool water and extracted withethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. Theresulting product was purified by silica gel chromatography (petroleumether:ethyl acetate=5:1) to give the title compound. LCMS: (ES⁺) m/z(M+23)⁺=560.3, tR=1.103.

Step 2—(±)-Allyl 2-(4-(3-aminooxetan-3-yl)phenyl)-4-methylpentanoate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-4-methyl-pentanoate (360 mg, 669 umol) in ethanol (10 mL) wasadded hydrochloric acid/dioxane (4 M, 836 uL) and the reaction mixturewas stirred at 0° C. for 30 min. On completion, the reaction mixture wasbasified with saturated sodium bicarbonate solution until pH=8 andextracted with dichloromethane (3×30 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound. LCMS: (ES⁺) m/z (2M+H)⁺=607.5, tR=0.754.

(±)-Allyl 2-[4-(3-aminooxetan-3-yl)phenyl]-3-cyclopropyl-propanoate(Intermediate CO)

Step 1—(±)-Allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-3-cyclopropyl-propanoate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate(1.00 g, 2.08 mmol, synthesized via Steps 1-2 of Intermediate BT) andsodium iodide (31.1 mg, 208 umol) in N,N-dimethylformamide (30 mL) wasadded LiHMDS (1 M, 3.12 mL) at 0° C. The reaction mixture was stirred at0° C. for 30 min. Bromomethylcyclopropane (2.81 g, 20.8 mmol) was addedto the reaction mixture and the mixture was stirred at rt for 16 hrs. Oncompletion, the mixture was quenched with ammonium chloride solution (80mL) and extracted with ethyl acetate (2×100 mL). The combined organiclayer was washed with brine (100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a residue. Theresidue was purified with silica gel chromatography (petroleumether:ethyl acetate=3:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ=7.59 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 5.98-5.82 (m,1H), 5.42-5.35 (m, 1H), 5.31-5.15 (m, 3H), 4.90 (d, J=6.1 Hz, 1H),4.79-4.69 (m, 2H), 4.67-4.49 (m, 2H), 3.86 (d, J=11.3 Hz, 1H), 3.76 (t,J=7.7 Hz, 1H), 3.36 (t, J=8.2 Hz, 2H), 1.98-1.88 (m, 1H), 1.79 (dtd,J=4.2, 6.7, 13.8 Hz, 1H), 1.38 (s, 9H), 0.97-0.82 (m, 2H), 0.73-0.60 (m,1H), 0.47-0.34 (m, 2H), 0.18-0.04 (m, 2H), 0.00 (s, 9H).

Step 2—(±)-Allyl2-[4-(3-aminooxetan-3-yl)phenyl]-3-cyclopropyl-propanoate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]-3-cyclopropyl-propanoate (950 mg, 1.77 mmol) in ethanol (2 mL)was added hydrogen chloride/dioxane (4 M, 20 mL) at 0° C. The reactionmixture was stirred at 0° C. for 3 hrs. On completion, the reactionmixture was neutralized with saturated sodium bicarbonate solution topH=8, and extracted with dichloromethane (2×70 mL). The combined organiclayer was concentrated in vacuo to give the title compound. LCMS: (ES⁺)m/z (M-NH₂)⁺=285.0, tR=0.907.

(4-Iodocyclohexyl) acetate (Intermediate CP)

Step 1—(4-Hydroxycyclohexyl) acetate

To a solution of cyclohexane-1,4-diol (20.0 g, 172 mmol) intetrahydrofuran (20 mL) was added triethylamine (52.3 g, 516 mmol) andacetyl chloride (14.8 g, 189 mmol) dropwise, and the mixture was stirredat rt for 0.5 hr. On completion, the mixture was diluted with saturatedammonium chloride (10 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layer was washed with brine (3×20 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by chromatography on silica gel (petroleum ether:ethylacetate=10:1 to 1:1) to give the title compound. ¹H NMR (400 MHz, CDCl3)δ=4.88-4.65 (m, 1H), 3.85-3.61 (m, 1H), 2.08-2.00 (m, 3H), 2.00-1.95 (m,1H), 1.91-1.81 (m, 1H), 1.77-1.49 (m, 4H), 1.50-1.38 (m, 2H).

Step 2—(4-Iodocyclohexyl) acetate

To a solution of triphenylphosphine (11.6 g, 44.5 mmol) indichloromethane (15 mL) was added imidazole (3.03 g, 44.5 mmol) at 0° C.Iodine (11.3 g, 44.5 mmol) was added at rt and the mixture was stirredfor 0.5 hr. Then (4-hydroxycyclohexyl) acetate (4.70 g, 29.7 mmol) wasadded to the mixture and the mixture was stirred at rt for 1 hr. Oncompletion, the mixture was diluted with saturated ammonium chloride (20mL) and extracted with ethyl acetate (3×30 mL). The combined organiclayer was washed with brine (3×20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 7:1)to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=4.96-4.76 (m, 1H),4.53-4.21 (m, 1H), 2.28-2.13 (m, 2H), 2.05 (d, J=18.3 Hz, 3H), 2.01-1.81(m, 4H), 1.77-1.66 (m, 1H), 1.58-1.47 (m, 1H).

Allyl 2-(4-acetoxycyclohexyl)-2-[4-(3-aminooxetan-3-yl)phenyl]acetate(Intermediate CQ)

Step 1—(±)-Allyl2-(4-acetoxycyclohexyl)-2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate

To a solution of allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (800 mg, 1.66 mmol, synthesized via Steps 1-2 ofIntermediate BT) in dimethyl formamide (15 mL) was added lithiumbis(trimethylsilyl)amide (1 M, 8.30 mL, 8.3 mmol) at rt.(4-Iodocyclohexyl) acetate (1.34 g, 4.98 mmol) was added dropwise, andthe mixture was stirred at rt for 2 hrs under nitrogen atmosphere. Oncompletion, the mixture was diluted with saturated ammonium chloride (30mL) and extracted with ethyl acetate (3×30 mL). The combined organiclayer was washed with brine (3×20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=10:1 to 5:1)to give the title compound. ¹H NMR (400 MHz, CDCl3) δ=7.57 (d, J=7.9 Hz,2H), 7.39 (t, J=9.0 Hz, 2H), 5.94-5.79 (m, 1H), 5.73-5.48 (m, 1H), 5.37(t, J=6.8 Hz, 1H), 5.28-5.20 (m, 2H), 4.98 (br. s., 1H), 4.90-4.82 (m,1H), 4.72 (d, J=7.0 Hz, 2H), 4.65-4.58 (m, 1H), 4.54-4.46 (m, 1H), 4.12(q, J=7.1 Hz, 1H), 3.83 (d, J=10.5 Hz, 1H), 3.34 (t, J=8.3 Hz, 2H), 2.04(s, 3H), 1.95-1.82 (m, 2H), 1.80-1.64 (m, 2H), 1.41 (d, J=12.8 Hz, 2H),1.35 (s, 9H), 1.22-1.11 (m, 2H), 0.95-0.81 (m, 3H), 0.00 (s, 9H).

Step 2—(±)-Allyl2-(4-acetoxycyclohexyl)-2-[4-(3-aminooxetan-3-yl)phenyl]acetate

To a solution of (±)-allyl2-(4-acetoxycyclohexyl)-2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (350 mg, 562 umol) in ethanol(20 mL) was added hydrochloric acid (4 M in dioxane, 1.13 mL), themixture was stirred at 0° C. for 2 hrs. On completion, the mixture wasadjusted pH to 8-9 with ammonia in water (30%) and concentrated invacuo. The residue was purified by chromatography on silica gel(petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=30:1) togive the title compound. LCMS: (ES⁺) m:z (M+H)⁺=388.2, tR=0.653.

(±)-Allyl 3-[4-(3-aminooxetan-3-yl)phenyl]tetrahydrofuran-3-carboxylate(Intermediate CR)

Step 1—(±)-Allyl3-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]tetrahydrofuran-3-carboxylate

To a solution of (±)-allyl2-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]acetate (200 mg, 415 umol, synthesized via Steps 1-2 ofIntermediate BT) in N,N-dimethylformamide (10 mL) was added sodiumhydride (41.5 mg, 1.04 mmol) and 1-chloro-2-(chloromethoxy)ethane (64.3mg, 498 umol) in one portion at 0° C., and the reaction was stirred at15° C. for 12 hrs. On completion, the solution was poured into water (30mL), and extracted with ethyl acetate (3×20 mL). The combined organicphase was washed with brine (3×20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=100:1-10:1) to givethe title compound. LCMS: (ES⁺) m/z (M+23)⁺=560.2, tR=0.984.

Step 2—(±)-Allyl3-[4-(3-aminooxetan-3-yl)phenyl]tetrahydrofuran-3-carboxylate

To a solution of (±)-allyl3-[4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]phenyl]tetrahydrofuran-3-carboxylate (60.0 mg, 112 umol) in ethanol (5mL) was added hydrochloric/dioxane (4 M/L10.0 g, 1.12 mmol) in oneportion at 0° C., and the reaction was stirred at 0° C. for 1 hr. Oncompletion, the reaction was concentrated in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M+23)⁺=326.1, tR=0.794.

N-((4-(3-aminooxetan-3-yl)phenyl)sulfonyl)propionamide (Intermediate CS)

Step 1—Benzyl (3-(4-(N-propionylsulfamoyl)phenyl)oxetan-3-yl)carbamate

To a solution of propionic acid (214 mg, 2.90 mmol, 216 uL), EDCI (555mg, 2.90 mmol) and DMAP (471 mg, 3.86 mmol) in N,N-dimethylformamide (10mL) was added benzyl N-[3-(4-sulfamoylphenyl)oxetan-3-yl]carbamate (350mg, 965 umol, synthesized via Steps 1-5 of Intermediate BY) at rt. Thereaction mixture was stirred at rt for 24 hrs. On completion, thereaction mixture was concentrated in vacuo. To the residue was addeddichloromethane (20 mL) then it was washed with citric acid (10 mL). Theorganic layer was washed with brine (5 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The resulting product was purifiedby silica gel chromatography (dichloromethane:methanol=50:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=419.2, tR=0.737.

Step 2—N-((4-(3-aminooxetan-3-yl)phenyl)sulfonyl)propionamide

To a solution of benzylN-[3-[4-(propanoylsulfamoyl)phenyl]oxetan-3-yl]carbamate (460 mg, 1.10mmol) in methanol (5 mL) was added Pd—C(10%, 50 mg) under nitrogen. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes at rt. The mixture was stirred under hydrogen (50 psi) at 50° C.for 32 hours. On completion, the mixture was extracted withdichloromethane (2×30 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound. LCMS: (ES⁺) m/z (2M+H)⁺=569.4, tR=0.271.

4-(3-Aminooxetan-3-yl)-N-(methylsulfonyl)benzamide (Intermediate CT)

Step1—(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)-propane-2-sulfinamide

To a solution of(±)-N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide(17.0 g, 51.1 mmol, synthesized via Steps 1-2 of Intermediate AE) intetrahydrofuran (300 mL) was added sodium hydride (4.09 g, 102 mmol,60%) at 0° C. and the reaction mixture was stirred for 0.5 hr. ThenSEMCl (12.8 g, 76.7 mmol) was added dropwise and the reaction mixturewas stirred at rt for 0.5 hr. On completion, the reaction mixture waspoured into 1000 mL ice-water. The aqueous phase was extracted withdichloromethane (3×1000 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. The solidwas purified by silica gel chromatography (petroleum ether:ethylacetate=5:1) to give title compound. ¹H NMR (400 MHz, CDCl3) δ=7.61-7.49(m, 4H), 5.38 (d, J=6.4 Hz, 1H), 5.26 (d, J=6.8 Hz, 1H), 4.84 (d, J=6.4Hz, 1H), 4.72 (d, J=10.7 Hz, 1H), 4.68 (d, J=10.5 Hz, 1H), 3.82 (d,J=10.5 Hz, 1H), 3.39-3.31 (m, 2H), 1.37 (s, 9H), 0.93-0.85 (m, 2H), 0.02(s, 9H).

Step 2—Ethyl4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)benzoate

To a mixture ofN-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-N-(2-trimethylsilylethoxymethyl)propane-2-sulfinamide(9.00 g, 19.5 mmol) and triethylamine (9.85 g, 97.3 mmol) in ethanol (90mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (1.59 g, 1.95 mmol) in one portionunder a nitrogen. The mixture was flushed with CO (50 psi) three times,then the reaction mixture was heated to 80° C. and stirred for 16 hours.On completion, the reaction mixture was filtered and concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=20:1) to give the title compound. LCMS: (ES⁺) m/z(M+23)⁺=478.3, tR=0.999.

Step3—4-(3-(2-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)benzoic acid

To a solution of ethyl4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]benzoate(5.00 g, 11.0 mmol) in tetrahydrofuran (30 mL) and water (10 mL) wasadded LiOH (1.31 g, 54.9 mmol) at rt. The reaction mixture was stirredat rt for 24 hrs. On completion, the reaction mixture was concentratedin vacuo to remove the tetrahydrofuran. The residue was diluted withwater (10 mL), then citric acid (1N, 20 mL) was added to pH=7 slowly.The mixture was then filtered and concentrated in vacuo to dryness togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=13.05 (br. s., 1H),8.00 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 5.21 (d, J=6.5 Hz, 1H),5.06 (d, J=7.0 Hz, 1H), 4.86 (d, J=6.5 Hz, 1H), 4.78 (d, J=6.8 Hz, 1H),4.51 (d, J=10.8 Hz, 1H), 3.88 (d, J=10.5 Hz, 1H), 3.32-3.24 (m, 2H),1.27 (s, 9H), 0.82 (t, J=7.9 Hz, 2H), 0.00 (s, 9H).

Step4—4-(3-(2-Methyl-N-((2-(trimethylsilyl)ethoxy)methyl)propan-2-ylsulfinamido)oxetan-3-yl)-N-(methylsulfonyl)benzamide

To a solution of4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]benzoicacid (1.00 g, 2.34 mmol) in N,N-dimethylformamide (20 mL) was added EDCI(1.35 g, 7.02 mmol) at 0° C. and the mixture was stirred for 0.5 hr.Then methanesulfonamide (334 mg, 3.51 mmol) and N,N-dimethylpyridine(857 mg, 7.02 mmol) were added at 0° C. The reaction mixture was stirredat rt for 12 hrs. On completion, the reaction was concentrated in vacuo,and the residue was purified by prep-HPLC [prep-HPLC (column: Daiso250*50 mm, 10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 55ACN%-75ACN %, 28 min; 55% min)] to give the title compound. LCMS: (ES⁺) m/z(M+23)⁺=527.3, tR=0.888

Step 5—4-(3-Aminooxetan-3-yl)-N-(methylsulfonyl)benzamide

To a solution of4-[3-[tert-butylsulfinyl(2-trimethylsilylethoxymethyl)amino]oxetan-3-yl]-N-methyl-sulfonyl-benzamide(250 mg, 495 umol) in ethanol (10 mL) was added HCl/dioxane (4 M, 619uL) and the reaction mixture was stirred at 0° C. for 1 hr. The reactionmixture was basified with saturated sodium bicarbonate solution untilpH=8 and extracted with dichloromethane (3×20 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give the title compound. LCMS: (ES⁺) m/z (M+23)⁺=293.1,tR=0.108.

General Methods Example 1 (Method1)—N-(1-(N-acetylsulamoyl)-4-phenylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Step 1—Tert-butyl4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-4-phenylpiperidine-1-carboxylate

To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (1.78 g,7.29 mmol) in dichloromethane (6.00 mL) was added N, N-dimethylformamide(53.3 mg, 729 umol), followed by oxalyl dichloride (1.85 g, 14.6 mmol)at rt. The mixture was then heated to 40° C. and stirred for 30 mins. Oncompletion, the mixture was concentrated in vacuo to give a the titlecompound (1.90 g, 95% yield), which was used into the next step directlywithout further purification.

To a mixture of tert-butyl 4-amino-4-phenyl-piperidine-1-carboxylate(1.00 g, 3.62 mmol) and triethylamine (1.83 g, 18.1 mmol) indichloromethane (10 mL) was added4,5-dichloro-1-methyl-indole-2-carbonyl chloride (1.14 g, 4.34 mmol) at0° C. The mixture was then warmed to rt and stirred for 16 hrs. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue, which was purified by column chromatography(eluent: petroleum ether:ethyl acetate=10:1 to 2:1) to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ=8.65 (br. s, 1H), 7.58 (d, J=8.8Hz, 1H), 7.47-7.32 (m, 7H), 3.91 (d, J=12.8 Hz, 2H), 3.86 (s, 3H),3.21-3.05 (m, 2H), 2.61 (d, J=12.8 Hz, 2H), 1.84 (t, J=12.8 Hz, 2H),1.42 (s, 9H).

Step2—4,5-Dichloro-1-methyl-N-(4-phenylpiperidin-4-yl)-1H-indole-2-carboxamidehydrochloride

To a mixture of tert-butyl4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-phenyl-piperidine-1-carboxylate(800 mg, 1.59 mmol) in methanol (2 mL) was added a solution of 4 Mhydrogen chloride in methanol (5 mL) at rt. The mixture was stirred atrt for 3 hrs. On completion, the mixture was concentrated in vacuo togive the title compound, which was used into the next step directly.

Step 3—Tert-butyl(4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-4-phenylpiperidin-1-yl)sulfonylcarbamate

To a solution of4,5-dichloro-1-methyl-N-(4-phenyl-4-piperidyl)indole-2-carboxamide-hydrochloride(700 mg, 1.60 mmol) and triethylamine (807 mg, 7.98 mmol) indichloromethane (10 mL) was added tert-butyl N-chlorosulfonylcarbamate(344 mg, 1.60 mmol) portion-wise at 0° C. The resultant mixture waswarmed to rt and stirred for 16 hrs. On completion, water (20 mL) wasadded to the mixture, which was then extracted with dichloromethane(3×20 mL). The combined dichloromethane phase was washed by brine (50mL), dried over sodium sulfate, and concentrated in vacuo to give aresidue, which was purified by column chromatography (petroleum:ethylacetate=10:1 to 2:1) to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ=8.71 (br. s, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.47-7.21 (m, 7H),3.87 (s, 3H), 3.60 (d, J=12.3 Hz, 2H), 3.23 (t, J=5.7 Hz, 2H), 2.71 (d,J=12.9 Hz, 2H), 1.99 (t, J=10.2 Hz, 2H), 1.32 (s, 9H).

Step4—4,5-Dichloro-1-methyl-N-(4-phenyl-1-sulfamoylpiperidin-4-yl)-1H-indole-2-carboxamide)

To a solution of tert-butylN-[[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-phenyl-1-piperidyl]sulfonyl]carbamate(400 mg, 688 umol) in methanol (3 mL) and dichloromethane (3 mL) wasadded a solution of 4 M hydrogen chloride in methanol (4 mL) at rt. Themixture was stirred at rt for 2 hrs. On completion, the mixture wasconcentrated in vacuo to give a crude yellow solid which was purified bycolumn chromatography (dichloromethane:methanol=100:1 to 10:1) to givethe title compound. LCMS (ES⁺) m/z (M−H)=479, tR=1.183.

Step5—N-(1-(N-acetylsulamoyl)-4-phenylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a solution of4,5-dichloro-1-methyl-N-(4-phenyl-1-sulfamoyl-4-piperidyl)indole-2-carboxamide(130 mg, 270 umol) and triethylamine (54.7 mg, 540 umol) indichloromethane (5 mL) was added acetyl chloride (31.8 mg, 405 umol)dropwise at 0° C. The resultant mixture was stirred for 16 hrs at rt. Oncompletion, methanol (1 mL) was added to the mixture and the resultingmixture was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (Condition: water (0.05% ammonia hydroxidev/v)-ACN; Column: Phenomenex Gemini C18 250*50 10 u) to give the titlecompound. LCMS (ES⁻) m/z=521.1 (M−1), tR=1.034. ¹HNMR (400 MHz, MeOD-d₆)δ=8.68 (br. s, 1H), 7.51 (dd, J=8.4, 1.2 Hz, 2H), 7.45-7.36 (m, 4H),7.29-7.25 (m, 2H), 3.88 (s, 3H), 3.87-3.80 (m, 2H), 3.45-3.39 (m, 2H),2.73 (d, J=12.4 Hz, 2H), 2.17 (td, J=14.0, 4.8 Hz, 2H), 2.08 (s, 3H).

Example2—N-(4-(3-acetamidophenyl)-1-(N-acetylsulfamoyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

N-(4-(3-acetamidophenyl)-1-(N-acetylsulfamoyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamidewas synthesized via Method 1 with acid A and amine S. The residue fromthe final step was purified by prep-HPLC (Condition: water (0.05%ammonia hydroxide v/v)-ACN; Column: Phenomenex Gemini C18 250*50 10 u)to give the title compound. LCMS (ES⁺) m/z=602 (M+23), tR=0.98. ¹HNMR(400 MHz, MeOD-d₆) δ=7.82 (t, J=1.6 Hz, 1H), 7.46-7.38 (m, 3H), 7.33 (t,J=8.0 Hz, 1H), 7.26-7.23 (m, 2H), 3.90 (s, 3H), 3.79 (d, J=12.8 Hz, 2H),3.45-3.38 (m, 2H), 2.70 (d, J=12.8 Hz, 2H), 2.21-2.13 (m, 5H), 2.09 (s,3H).

Example3—4,5-Dichloro-1-methyl-N-[4-phenyl-1-(pyrazin-2-ylsulfamoyl)-4-piperidyl]indole-2-carboxamide

To a solution of4,5-dichloro-1-methyl-N-(4-phenyl-4-piperidyl)indole-2-carboxamide (100mg, 248 umol, synthesized via Method 1, Steps 1-2 as seen in Example 1)in anhydrous acetonitrile (3 mL) was added triethylamine (251 mg, 2.49mmol). The mixture was stirred at rt for 30 mins. Then,2-oxo-N-pyrazin-2-yl-oxazolidine-3-sulfonamide (91.0 mg, 372 umol) wasadded and the mixture was transferred to a microwave tube. The sealedtube was heated at 130° C. for 150 minutes under microwave. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (Condition: 0.1% TFA-ACN; Column: WelchUltimate AQ-C18 150*30 mm; Particle size: 5 um) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=559.2, tR=0.910. ¹H NMR (400 MHz,DMSO-d₆) δ=11.01 (br. s., 1H), 8.66 (s, 1H), 8.43 (d, J=1.0 Hz, 1H),8.27-8.20 (m, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H),7.44-7.39 (m, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.27-7.21 (m, 1H), 7.14 (s,1H), 3.83 (s, 3H), 3.67 (d, J=12.8 Hz, 2H), 3.26 (t, J=11.9 Hz, 2H),2.72-2.61 (m, 2H), 2.01-1.87 (m, 2H).

Example4—N-(1-(N-acetylsulfamoyl)-4-(3-cyanophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a solution of tert-butyl4-(3-bromophenyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]piperidine-1-carboxylate (950 mg, 1.63 mmol, synthesized viaMethod 1 with acid A and amine Q) in 1-methylpyrrolidin-2-one (15 mL)was added copper cyanide (730 mg, 8.15 mmol) at rt. The reaction mixturewas stirred at 120° C. for 12 hrs. On completion, the reaction mixturewas poured onto ice and extracted with ethyl acetate (3×200 mL). Theorganic layers were combined, washed with brine (50 mL), andconcentrated in vacuo. The crude product was purified by silica gelchromatography (petroleum ether:ethyl acetate=10:1) to give tert-butyl4-(3-cyanophenyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]piperidine-1-carboxylate.LCMS: (ES⁺) m/z (M−H)⁻=525.2, tR=1.497. From tert-butyl4-(3-cyanophenyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]piperidine-1-carboxylate the final product was then made viaMethod 1, Steps 2-5 to yieldN-(1-(N-acetylsulfamoyl)-4-(3-cyanophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide.LCMS: (ES⁻) m/z (M−H)⁻=546.0, tR=1.377. ¹H NMR (400 MHz, MeOD)δ=7.90-7.83 (m, 2H), 7.68-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7.48-7.34 (m,3H), 7.32-7.27 (m, 2H), 3.89 (s, 3H), 3.76 (d, J=12.4 Hz, 2H), 3.16 (q,J=7.4 Hz, 2H), 2.69 (d, J=11.4 Hz, 2H), 2.22-2.14 (m, 2H), 2.05 (s, 3H).

Example5—N-(4-(3-Acetamidophenyl)-1-acetylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a solution ofN-[4-(3-acetamidophenyl)-4-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamidehydrochloride (350 mg, 706 umol, synthesized via Method 1, Steps 1-2with acid and amine S as starting materials as seen in Example 2) andtriethylamine (357 mg, 3.53 mmol) in dichloromethane (5.00 mL) was addedacetyl chloride (83.1 mg, 1.06 mmol) dropwise at 0° C. The reactionmixture was warmed to rt and stirred for 0.5 hrs. On completion, water(10 mL) was added to the mixture and the organics were then extractedwith dichloromethane (3×10 mL). The combined dichloromethane phase waswashed with brine (30 mL) and dried over sodium sulfate. The combineddichloromethane phase was concentrated in vacuo. The residue waspurified by prep-HPLC (condition: 0.1% TFA-ACN; column: Welch UltimateAQ-C18 150*30 mm*5 um) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=501.1, tR=0.989. ¹H NMR (400 MHz, DMSO-d6) δ=9.94 (br. s., 1H),8.75 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.47-7.43 (m, 2H),7.40 (s, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 4.35 (d,J=13.2 Hz, 1H), 3.88 (s, 3H), 3.80 (d, J=13.2 Hz, 1H), 3.43 (t, J=12.4Hz, 1H), 2.94 (t, J=12.4 Hz, 1H), 2.60 (t, J=14.8 Hz, 2H), 2.06 (s, 3H),2.03 (s, 3H), 1.91 (td, J=13.6 Hz, 1H), 1.74 (td, J=12.8, 3.6 Hz, 1H).

Example 6 (Method2)—(±)-4,5-dichloro-1-methyl-N-[1-(methylcarbamoylsulfamoyl)-3-phenyl-3-piperidyl]indole-2-carboxamide

Step1—(±)-N-[1-benzyl-3-(3-bromophenyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (1.06 g,4.35 mmol) in dichloromethane (10 mL) was added oxalyl chloride (1.10 g,8.70 mmol) and dimethylformamide (21.2 mg, 290 umol). The mixture wasstirred at rt for 1 hr. On completion, the solution was concentratedunder reduce pressure to give a residue. The residue was dissolved indichloromethane (10 mL) and added into a solution of(±)-1-benzyl-3-(3-bromophenyl)piperidin-3-amine (1.00 g, 2.90 mmol) andtriethylamine (880 mg, 8.70 mmol), and the mixture was stirred at rt 1hr. On completion, the reaction mixture was quenched with water (100 mL)at 0° C., and extracted with dichloromethane (3×100 mL). The combinedorganic layers were washed with aqueous sodium chloride (2×50 mL), driedover sodium chloride, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (petroleumether:ethyl acetate=5:1 to 1:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ=7.55 (s., 1H), 7.43-7.40 (m, 4H), 7.37-7.32 (m, 5H),7.23-7.19 (m, 2H), 7.06 (s, 1H), 3.97 (s, 3H), 3.64 (d, J=12.8 Hz, 1H),3.50 (d, J=12.8 Hz, 1H), 3.01 (d, J=10.8 Hz, 1H), 2.78-2.77 (m, 2H),2.1-1.80 (m, 5H).

Step2—(±)-4,5-dichloro-1-methyl-N-(3-phenyl-3-piperidyl)indole-2-carboxamide

To a solution of(±)-N-[1-benzyl-3-(3-bromophenyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide(450 mg, 788 umol) in ethyl acetate (5 mL) was added Pd/C (300 mg, 788umol). The suspension was degassed under vacuum and purged with hydrogenseveral times. The mixture was stirred under hydrogen (15 psi) at 25° C.for 12 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=402.1, tR=1.584.

Step3—(±)-tert-butyl-N-[[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-phenyl-1-piperidyl]sulfonyl]carbamate

To a solution of(±)-4,5-dichloro-1-methyl-N-(3-phenyl-3-piperidyl)indole-2-carboxamide(350 mg, 869 umol) in dichloromethane (2 mL) was added triethylamine(264 mg, 2.61 mmol) and tert-butyl N-chlorosulfonylcarbamate (281 mg,1.30 mmol). The mixture was stirred at rt for 1 hour. On completion, thereaction mixture was quenched by the addition of hydrochloric acid (1 N,10 mL) at 0° C., the solution was then diluted with dichloromethane (100mL) separated and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with aqueous sodium chloride (2×25 mL), driedover sodium sulfate, filtered and concentrated in vacuo to give thetitle compound. LCMS: (ES⁺) m/z (M+23)⁺=603.1, tR=0.897.

Step4—(±)-4,5-dichloro-1-methyl-N-(3-phenyl-1-sulfamoyl-3-piperidyl)indole-2-carboxamide

A solution of(±)-tert-butyl-N-[[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-phenyl-1-piperidyl]sulfonyl]carbamate(300 mg, 516 umol) in hydrogen chloride/methanol (5 mL) was stirred atrt for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=483.1,tR=0.800.

Step5—(±)-4,5-dichloro-1-methyl-N-[i-(methylcarbamoylsulfamoyl)-3-phenyl-3-piperidyl]indole-2-carboxamide

To a solution of(±)-4,5-dichloro-1-methyl-N-(3-phenyl-1-sulfamoyl-3-piperidyl)indole-2-carboxamide (200 mg, 386 umol) in dichloromethane (5 mL) wasadded triethylamine (117 mg, 1.16 mmol) and N-methylcarbamoyl chloride(54.2 mg, 579 umol). The mixture was stirred at rt for 1 hour. Oncompletion, the reaction mixture was quenched by the addition ofhydrochloric acid (1 N, 10 mL) at 0° C. The solution was then dilutedwith water (50 mL), extracted with dichloromethane (3×50 mL), and driedover anhydrous sodium sulfate. The combined organic layers were filteredand concentrated in vacuo to give a residue. The residue was purified bypre-HPLC (Phenomenex Gemini C18 250*50 10 u, water (0.05% ammoniahydroxide)-ACN) and lyophilized in vacuo to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=538.1, tR=0.894. ¹H NMR (400 MHz, MeOD) δ=7.58(d, J=7.6 Hz, 2H), 7.41-7.36 (m, 5H), 7.30-7.25 (m, 1H), 4.13-4.10 (m,1H), 3.89 (s, 3H), 3.81-3.78 (m, 1H), 3.33-3.32 (m, 1H), 3.09-2.86 (m,2H), 2.64 (s, 3H), 2.10-1.80 (m, 3H).

Example7—(±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide

Step1—(±)-N-[1-benzyl-3-(3-cyanophenyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of(±)-N-(1-benzyl-3-(3-bromophenyl)piperidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide(700 mg, 1.23 mmol, synthesized via Step 1 of Method 2 as seen above inExample 6) in dimethyl formamide (5 mL) was added zinc cyanide (433 mg,3.69 mmol) and tetrakis (triphenylphosphine) palladium (142 mg, 123umol). The mixture was stirred at 120° C. for 2 hours under nitrogenatmosphere. On completion, the reaction mixture was quenched by additionof water (100 mL) at 0° C., and then extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (2×50 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a residue. The residue was purified by column chromatography(petroleum ether:ethyl acetate=5:1 to 1:1) to give the title compound.¹H NMR (400 MHz, CDCl3) δ=7.70 (s., 1H), 7.50 (d, J=8.0 Hz, 1H), 7.44(d, J=6.8 Hz, 2H), 7.42-7.39 (m, 7H), 7.22 (d, J=8.8 Hz, 1H), 7.06 (s,1H), 3.96 (s, 3H), 3.77 (d, J=13.2 Hz, 1H), 3.58 (d, J=13.2 Hz, 1H),3.05 (d, J=11.2 Hz, 1H), 2.80-2.77 (m, 2H), 2.21-1.80 (m, 5H).

Step2—(±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-3-piperidyl]-1-methyl-indole-2-carboxamide

To a solution of(±)-N-(1-benzyl-3-(3-cyanophenyl)piperidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide(500 mg, 966 umol) in 1,2-dichloroethane (2 mL) was added 1-chloroethylcarbonochloridate (2.76 g, 19.3 mmol), and the mixture was stirred at90° C. for 12 hours. On completion, the reaction mixture wasconcentrated in vacuo. Then methanol (10 mL) was added to the residueand the solution was stirred at 80° C. for 1 hr. The solution was thenconcentrated in vacuo to remove methanol. The residue was diluted withwater (30 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound, which was used into next step without further purification.LCMS: (ES⁺) m/z (M+H)⁺=427.1, tR=0.753.

Step3-5—(±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide

(±)-4,5-Dichloro-N-[3-(3-cyanophenyl)-3-piperidyl]-1-methyl-indole-2-carboxamidewas brought on to the final product via Steps 3-5 of Method 2 to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=563.0, tR=0.93. ¹H NMR (400MHz, DMSO-d₆) δ=10.27 (br. s., 1H), 8.65 (s, 1H), 8.05-7.96 (m, 1H),7.95-7.85 (m, 1H), 7.74 (d, J=7.78 Hz, 1H), 7.64-7.52 (m, 2H), 7.45 (d,J=8.78 Hz, 1H), 7.39-7.33 (m, 1H), 6.87 (br. s., 1H), 6.31 (br. s., 1H),3.97-3.87 (m, 2H), 3.87-3.82 (m, 3H), 3.47-3.37 (m, 1H), 3.15 (t, J=9.03Hz, 1H), 2.56 (d, J=4.27 Hz, 3H), 2.32 (d, J=9.29 Hz, 1H), 2.06 (t,J=9.79 Hz, 1H), 1.91-1.78 (m, 1H), 1.58-1.40 (m, 1H).

Example 8 (Method3)—(±)-N-[1-(acetylsulfamoyl)-3-phenyl-pyrrolidin-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

Step1—(±)-(1-Benzyl-3-phenyl-pyrrolidin-3-yl)-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (500 mg,2.05 mmol) in a mixture of dichloromethane (20 mL) andN,N-dimethylformamide (157 uL) was added oxalyl chloride (1.04 g, 8.19mmol) dropwise and the reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give4,5-dichloro-1-methyl-indole-2-carbonyl chloride, which was used in thenext step directly.

To a solution of (±)-1-benzyl-3-phenyl-pyrrolidin-3-amine (500 mg, 1.98mmol) in dichloromethane (10 mL) was added4,5-dichloro-1-methyl-indole-2-carbonyl chloride (500 mg, 1.98 mmol) andtriethylamine (601 mg, 5.94 mmol). The reaction was stirred at rt for 12hrs. On completion, the reaction was diluted with saturated ammoniumchloride (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The reaction was purified by chromatography onsilica gel (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=30:1) to give the title compound. LCMS: (ES⁺)m:z (M+H)⁺=478.2.

Step2—(±)-4,5-Dichloro-1-methyl-N-(3-phenylpyrrolidin-3-yl)indole-2-carboxamide

To the mixture of(±)-(1-benzyl-3-phenyl-pyrrolidin-3-yl)-4,5-dichloro-1-methyl-indole-2-carboxamide(250 mg, 522 umol) in ethyl acetate (10 mL) was added Pd/C (10 mg, 10%),and the mixture was stirred at rt under hydrogen (50 psi) for 12 hrs. Oncompletion the mixture was filtered and the filtrate was concentrated invacuo. The residue was diluted with dichloromethane (30 mL), washed withsaturated sodium bicarbonate (10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (dichloromethane:methanol=30:1) to give thetitle compound. LCMS: (ES⁺) m:z (M+H)⁺=388.1.

Step3—(±)-N-[1-(acetylsulfamoyl)-3-phenyl-pyrrolidin-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-1-methyl-N-(3-phenylpyrrolidin-3-yl)indole-2-carboxamide(65 mg, 167 umol) in dichloromethane (5 mL) was added N-acetylsulfamoylchloride (52.7 mg, 334 umol) and triethylamine (67.7 mg, 669 umol), andthe mixture was stirred at rt for 2 hrs. On completion, the mixture wasdiluted with saturated ammonium chloride (10 mL), extracted withdichloromethane (3×20 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by prep-HPLC(YMC-Actus ODS-AQ 150*30 5 u, water (0.10% TFA)-ACN) and lyophilized invacuo to give the title compound. LCMS: (ES⁺) m:z (M+23)⁺=531.0,tR=0.873. ¹H NMR (400 MHz, DMSO-d6) δ=11.52 (s, 1H), 9.03 (s, 1H), 7.60(d, J=8.8 Hz, 1H), 7.46 (dd, J=8.2, 3H), 7.40 (s, 1H), 7.36 (t, J=7.7Hz, 2H), 7.28-7.24 (m, 1H), 4.22 (d, J=10.5 Hz, 1H), 3.93 (d, J=10.5 Hz,1H), 3.89 (s, 3H), 3.75 (d, J=7.8 Hz, 1H), 3.59-3.46 (m, 1H), 2.78-2.70(m, 1H), 2.25 (d, J=12.8 Hz, 1H), 1.84 (s, 3H).

Example9—N-(1-(N-acetylsulfamoyl)-3-phenylazetidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

N-(1-(N-acetylsulfamoyl)-3-phenylazetidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamidewas synthesized via Method 3 with acid A and amine U. In Step 2, 1 dropof HCl was added to catalyze the deprotection. The residue of the finalstep was purified by Prep-TLC (dichloromethane:methanol=15:1) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=495.0, tR=0.885. ¹H NMR (400MHz, MeOD) δ=7.62 (s, 1H), 7.60 (s, 1H), 7.49-7.38 (m, 4H), 7.37-7.30(m, 2H), 4.72 (d, J=8.8 Hz, 2H), 4.43 (d, J=8.8 Hz, 2H), 3.99 (s, 3H),2.06 (s, 3H).

Example 10 (Method4)—3-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl)benzoic acid

Step 1—Tert-butyl4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-4-(3-(ethoxycarbonyl)piperidine-1-carboxylate

To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (1.78 g,7.29 mmol) in dichloromethane (6.00 mL) was added N,N-dimethylformamide(53.3 mg, 729 umol), followed by oxalyl dichloride (1.85 g, 14.6 mmol)in one portion at rt. The mixture was heated to 40° C. and stirred for30 min. On completion, the mixture was concentrated in vacuo to give thetitle compound (crude).

To a mixture of tert-butyl4-amino-4-(3-ethoxycarbonylphenyl)piperidine-1-carboxylate (1.40 g, 4.02mmol) and triethylamine (1.22 g, 12.1 mmol) in dichloromethane (15.0 mL)was added 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (1.27 g, 4.82mmol) in three portions at rt. The mixture was stirred at rt for 16 hrs.On completion, the mixture was filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(petroleum ether:ethyl acetate=10:1 to 5:1) to give the title compound.¹H NMR (400 MHz, DMSO-d₆) δ=8.82 (br. s, 1H), 8.07 (s, 1H), 7.84 (d,J=7.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.52 (t,J=8.0 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 4.30 (q, J=7.2 Hz,2H), 3.94-3.85 (m, 2H) 3.85 (s, 3H), 3.16 (m, 2H), 2.61 (d, J=13.2 Hz,2H), 1.82-1.89 (m, 2H), 1.43 (s, 9H), 1.30 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 3-(4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl)benzoate hydrochloride

To a mixture of tert-butyl 4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-(3-ethoxycarbonylphenyl) piperidine-1-carboxylate (370 mg, 644umol) in ethyl acetate (3.00 mL) was added hydrogen chloride/ethylacetate (4M, 5.00 mL) in one portion at 0° C. The mixture was stirred atrt for 1 hr. On completion, the mixture was concentrated in vacuo togive the title compound which was used in the next step. LCMS: (ES⁺) m:z(M+H)⁺=474.1, tR=0.925.

Step 3—Ethyl3-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl) benzoate

To a mixture of ethyl3-[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoatehydrochloride (329 mg, 644 umol) and triethylamine (326 mg, 3.22 mmol)in dichloromethane (5.00 mL) was added N-acetylsulfamoyl chloride (101mg, 644 umol) in three portions at rt. The mixture was stirred at rt for2 hrs. On completion, to the mixture was added water (10 mL) and then itwas extracted with dichloromethane (3×10 mL). The combined organic phasewas washed with brine, dried over sodium sulfate, and concentrated invacuo to give a crude product which was purified by columnchromatography (petroleum ether:ethyl acetate=7:1 to 1:1) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ=11.53 (br. s, 1H), 8.87 (br.s, 1H), 8.06 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H),7.62 (d, J=8.8 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H),7.29 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 3.63 (d, J=12.0 Hz,2H), 3.28 (d, J=12.4 Hz, 2H), 2.67-2.70 (m, 2H), 2.01˜2.06 (m, 5H), 1.31(t, J=7.2 Hz, 3H).

Step4—3-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl)benzoic acid

To a mixture of ethyl3-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoate (140 mg, 235 umol) in tetrahydrofuran (3.00mL) was added the solution of lithium hydroxide (19.7 mg, 470 umol) inwater (3.00 mL) dropwise at rt. The mixture was stirred at rt for 16hrs. On completion, the mixture was concentrated in vacuo to give theaqueous phase which was cooled to 0° C., then hydrochloride solution(1N, 1 mL) was added to adjust pH to 4-5. The product was extracted withdichloromethane (3×10 mL). The combined organic phase was concentratedin vacuo to give the title product as a white solid (70 mg, 51% yield).LCMS (ESI⁻) m/z=565 (M−H), tR=1.101. ¹H NMR (400 MHz, DMSO-d₆) δ=8.85(br. s, 1H), 8.05 (s, 1H), 7.83 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz,1H), 7.61 (d, J=8.4 Hz, 1H), 7.46-7.52 (m, 2H), 7.28 (s, 1H), 3.85 (s,3H), 3.63 (d, J=12.0 Hz, 2H), 3.27-3.30 (m, 2H), 2.69 (d, J=10.8 Hz,2H), 2.00 (m, 5H).

Example11—4-[1-(Acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoicacid

4-[1-(Acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoic acid was synthesized via Method 4 with acid A and amine Y. Theresidue of the final step was purified with prep-HPLC (Instrument: GX-D;Column: Boston Green ODS 150*30 5 u; Mobile phase: 0.225% formicacid-acetonitrile) to give the title compound. LCMS: (ES⁺) m/z(M+Na)⁺=589.0, tR=1.189. ¹H NMR (400 MHz, DMSO-d₆) δ=8.81 (s, 1H), 7.92(d, J=8.5 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.47(d, J=8.8 Hz, 1H), 7.31 (s, 1H), 3.85 (s, 3H), 3.59 (d, J=11.2 Hz, 2H),3.27-3.18 (m, 2H), 2.63-2.58 (m, 2H), 2.07-1.98 (m, 2H), 1.97 (s., 3H).

Example12—N-(1-(N-acetylsulfamoyl)-4-(3-(hydroxymethyl)phenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Step 1—Tert-butyl4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-4-(3-(hydroxymethyl)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-(3-ethoxycarbonylphenyl)piperidine-1-carboxylate(100 mg, 174 umol, synthesized via Method 1 as seen in Example 10) intetrahydrofuran (5.00 mL) was added lithium hydroboronate (11.4 mg, 522umol) at rt. The resultant mixture was stirred for 16 hrs. Oncompletion, water (3 mL) was added to the mixture and then it wasextracted with dichloromethane (3×5 mL). The combined dichloromethanephase was concentrated in vacuo to give a white solid. LCMS (ESI⁺) m/z(M−100)=432.1, tR=1.194.

Step2-3—N-(1-(N-acetylsulfamoyl)-4-(3-(hydroxymethyl)phenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Tert-butyl4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-4-(3-(hydroxymethyl)phenyl)piperidine-1-carboxylate was then converted to the final product viaMethod 4, Steps 2-3 to yield the title compound. LCMS (ESI⁻) m/z(M−1)=551.0, tR=1.368. ¹H NMR (400 MHz, DMSO-d₆) δ=8.71 (br. s, 1H),7.61 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.30-7.32(m, 2H), 7.28 (s, 1H), 7.19 (d, J=6.0 Hz, 1H), 5.19 (t, J=5.2 Hz, 1H),4.50 (d, J=4.8 Hz, 2H), 3.87 (s, 3H), 3.60 (d, J=12 Hz, 2H), 3.25 (t,J=12.4 Hz, 2H), 2.68 (d, J=12.4 Hz, 2H), 1.95-2.00 (m, 5H).

Example13—N-(1-(N-Acetylsulfamoyl)-4-(3-aminophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Step1—(±)-Tert-butyl-(3-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-4-yl)phenyl)carbamate

The mixture of(±)-3-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]benzoicacid (100 mg, 176 umol, Example 10) and 3 Å MS (400 mg) was dried invacuo to remove the water for 30 min. Then, the pre-dried solventtert-butanol (3.00 mL) was added, followed by triethylamine (23.2 mg,229 umol). The mixture was stirred for 30 min, and DPPA (6 drops) wasadded at rt. The reaction mixture was flushed with nitrogen three timesand heated to 90° C. with stirring for 16 hrs. On completion, themixture was concentrated in vacuo directly to give a residue which waspurified by column chromatography (petroleum ether:ethyl acetate=10:1 to5:1) to give the title compound as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=11.50 (br. s, 1H), 9.34 (br. s, 1H), 8.74 (br. s, 1H),7.74-7.72 (m, 1H), 7.63-7.60 (m, 1H), 7.49-7.38 (m, 2H), 7.27-7.20 (m,2H), 7.09-7.04 (m, 1H), 3.87 (s, 3H), 3.61 (d, J=12.0 Hz, 2H), 3.30-3.24(m, 2H), 2.64 (d, J=13.2 Hz, 2H), 2.00 (s, 3H), 1.97-1.91 (m, 2H), 1.46(s, 9H).

Step2—(±)-N-(1-(N-Acetylsulfamoyl)-4-(3-aminophenyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a mixture of (±)-tert-butylN-[3-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-4-piperidyl]phenyl]carbamate (50.0 mg, 78.3 umol) indichloromethane (1.00 mL) was added trifluoroacetic acid (153 mg, 1.34mmol) in one portion at rt. The mixture was stirred at rt for 16 hrs. Oncompletion, to the mixture was added sodium bicarbonate (sat. 10 mL) toadjust the pH=8. The product was extracted with dichloromethane (3×20mL). The combined dichloromethane phase was dried over sodium sulfateand concentrated in vacuo. The resulting residue was purified byprep-HPLC (condition: water (0.05% ammonia hydroxide v/v)-ACN; column:Phenomenex Gemini C18 250*50 10 u) to give the title compound. LCMS:(ES⁻) m/z (M−H)⁻=536.1, tR=2.201. ¹H NMR (400 MHz, DMSO-d₆) δ=8.52 (br.s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.27 (s, 1H),6.97 (t, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 6.42 (d,J=8.0 Hz, 1H), 4.99 (br. s, 2H), 3.88 (s, 3H), 3.55-3.50 (m, 2H), 3.11(t, J=12.0 Hz, 2H), 2.60 (d, J=13.2 Hz, 2H), 1.89-1.84 (m, 5H).

Example 14 (Method5)—(±)-3-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methylcarbamoylsulfamoyl)-3-piperidyl]benzoicacid

Step1—(±)-[1-Benzyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (400 mg,1.64 mmol) in a mixture of dichloromethane (20 mL) andN,N-dimethylformamide (150 uL) was added oxalyl chloride (1.04 g, 8.19mmol) dropwise and the reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give4,5-dichloro-1-methyl-indole-2-carbonyl chloride. To a solution of(±)-ethyl 3-(3-amino-1-benzyl-3-piperidyl)benzoate (309.77 mg, 1.18mmol) and triethylamine (100 mg, 991 umol) in dichloromethane (10 mL)was added a solution of 4,5-dichloro-1-methyl-indole-2-carbonyl chloride(400 mg, 1.18 mmol) in dichloromethane (5 mL) and the mixture wasstirred at rt for 12 hrs. On completion, the mixture was diluted withsaturated ammonium chloride (20 mL), extracted with dichloromethane(3×20 mL) and dried over anhydrous sodium sulfate, filtrated andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=10:1) to give the title compound. LCMS: (ES⁺)m:z (M+H)⁺=564.2, tR=0.760.

Step 2—(±)-Ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate

To a solution of(±)-[1-benzyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate(230 mg, 407 umol) in 1,2-dichloroethane (5 mL) was added 1-chloroethylcarbonochloridate (1.17 g, 8.15 mmol) and the reaction mixture wasstirred at 100° C. for 12 hrs. On completion, the reaction mixture wasconcentrated in vacuo. Methanol (5 mL) was added to the residue and themixture was stirred at 90° C. for 4 hrs. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1 todichloromethane:methanol=30:1) to give the title compound. LCMS: (ES⁺)m:z (M+H)⁺=474.2, tR=0.775.

Step 3—(±)-Ethyl3-[1-(tert-butoxycarbonylsulfamoyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate

To a solution of (±)-ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate(200 mg, 421 umol) in dichloromethane (30 mL) was added triethylamine(85.3 mg, 843.2 umol) and tert-butyl N-chlorosulfonylcarbamate (118 mg,548 umol), then the reaction mixture was stirred at rt for 0.5 hr. Oncompletion the mixture was concentrated in vacuo to give the titlecompound. LCMS: (ES⁺) m:z (M−55)⁺=597.1, tR=0.957.

Step 4—(±)-Ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-sulfamoyl-3-piperidyl]benzoate

To a mixture of (±)-ethyl3-[1-(tert-butoxycarbonylsulfamoyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-piperidyl]benzoate(270 mg, 413 umol) in ethyl acetate (5 mL) was added hydrochloricacid/ethyl acetate (4 M, 6 mL) and the reaction mixture was stirred atrt for 5 hrs. On completion, the mixture was concentrated in vacuo. Theresidue was diluted with dichloromethane (30 mL), washed with saturatedsodium bicarbonate (2×20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound. LCMS:(ES⁺) m:z (M+H)⁺=553.1, tR=0.879.

Step 5—(±)-Ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methylcarbamoyl-sulfamoyl)-3-piperidyl]benzoate

To a solution of (±)-ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-sulfamoyl-3-piperidyl]benzoate(170 mg, 307 umol) in dichloromethane (30 mL) was added triethylamine(310 mg, 426 uL, 3 mmol) and N-methylcarbamoyl chloride (143 mg, 1.54mmol) and the mixture was stirred at rt for 16 hrs. On completion, themixture was diluted with saturated ammonium chloride (20 mL), extractedwith dichloromethane (3×50 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by prep-TLC(dichloromethane:methanol=30:1) to give the title compound. LCMS: (ES⁺)m:z (M+H)⁺=611.1, tR=0.913.

Step6—(±)-3-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methylcarbamoyl-sulfamoyl)-3-piperidyl]benzoicacid

To a solution of (±)-ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methyl-carbamoylsulfamoyl)-3-piperidyl]benzoate(40.0 mg, 65.5 umol) in tetrahydrofuran (4 mL) and water (3 mL) wasadded lithium hydrate (6.28 mg, 262 umol) and the reaction mixture wasstirred at rt for 12 hrs. On completion, the mixture was adjusted pH to4-5 with hydrochloric acid (1 M), extracted with dichloromethane (3×20mL), dried over anhydrous sodium sulfate, filtrated and concentrated invacuo. The residue was purified by prep-HPLC (YMC-Actus ODS-AQ 150*30 5u, water (0.1% TFA)-ACN) to give the title compound. LCMS: (ES⁺) m:z(M+H)⁺=582.1, tR=0.821. ¹H NMR (400 MHz, DMSO-d₆) δ=12.98 (br. s., 1H),10.25 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.83 (d, J=7.53 Hz, 1H), 7.78(d, J=8.03 Hz, 1H), 7.58 (d, J=8.78 Hz, 1H), 7.49 (t, J=7.78 Hz, 1H),7.44 (d, J=8.78 Hz, 1H), 7.32 (s, 1H), 6.30 (d, J=4.27 Hz, 1H),4.14-4.23 (m, 1H), 3.83 (s, 3H), 3.58-3.67 (m, 1H), 3.50 (d, J=12.05 Hz,1H), 3.00-3.10 (m, 1H), 2.54 (d, J=4.52 Hz, 3H), 2.35-2.44 (m, 1H),1.85-2.00 (m, 2H), 1.53-1.62 (m, 1H).

Example15—(±)-4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)benzoic acid

(±)-4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)benzoic acid was synthesized via Method 5 withacid A and amine AA. After Step 2, a mixture of the methyl and ethylesters were formed. These were brought on as a mixture until the endwhen hydrolyzed in the final step. In Step 4, 4M HCl in MeOH was usedinstead of ethyl acetate as the solvent. In Step 6, MeOH used as thesolvent instead of THF. The residue of the final step was purified byprep-HPLC (Welch Ultimate AQ-C18 150*30 mm*5 um, 0.1% trifluoroaceticacid-acetonitrile) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=582.1, tR=0.806. ¹H NMR (400 MHz, DMSO-d₆) δ=10.28 (br. s., 1H),8.63 (s, 1H), 7.91 (d, J=8.28 Hz, 2H), 7.63 (d, J=8.41 Hz, 2H), 7.57 (d,J=8.91 Hz, 1H), 7.43 (d, J=8.78 Hz, 1H), 7.34 (s, 1H), 6.34 (d, J=4.14Hz, 1H), 4.12 (d, J=12.17 Hz, 1H), 3.83 (s, 3H), 3.66 (d, J=12.17 Hz,1H), 3.50 (m, 1H), 3.06 (t, J=9.60 Hz, 1H), 2.53 (d, J=4.52 Hz, 3H),2.41-2.29 (m, 1H), 2.03-1.80 (m, 2H), 1.57 (d, J=8.66 Hz, 1H).

Example16—(±)-4,5-Dichloro-N-[3-[3-(hydroxymethyl)phenyl]-1-(methylcarbamoyl-sulfamoyl)-3-piperidyl]-1-methyl-indole-2-carboxamide

To a solution of (±)-ethyl3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(methylcarbamoylsulfamoyl)-3-piperidyl]benzoate (40.0 mg, 65.52 umol, synthesized viaMethod 5, Steps 1-5 as seen in Example 14) in tetrahydrofuran (10 mL)was added lithium borohydride (4.28 mg, 196 umol), and the mixture wasstirred at rt for 12 hrs. On completion the mixture was diluted withsaturated ammonium chloride (20 mL), extracted with ethyl acetate (3×20mL), dried over anhydrous sodium sulfate, filtrated and concentrated invacuo. The residue was purified by prep-HPLC (YMC-Actus ODS-AQ 150*30 5u, water (0.1% TFA)-ACN) to give the title compound. LCMS: (ES⁺) m:z(M+H)⁺=568.0, tR=0.813. ¹H NMR (400 MHz, DMSO-d₆) δ=10.22 (br. s., 1H),8.49 (s, 1H) 7.58 (d, J=9.0 Hz, 1H), 7.45 (d, J=3.5 Hz, 2H), 7.38 (d,J=3.6 Hz, 1H), 7.27-7.33 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 6.23-6.33 (m,1H), 5.20 (br. s., 1H), 4.49 (d, J=4.3 Hz, 2H), 4.18 (d, J=12.6 Hz, 1H),3.85 (s, 3H), 3.47 (d, J=12.6 Hz, 1H), 2.99 (d, J=10.5 Hz, 2H),2.40-2.47 (m, 3H), 1.89 (d, J=10.3 Hz, 3H), 1.62 (br. s., 1H).

Example17—(±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-methyl-pyrrolidin-3-yl]benzoicacid

Step 1—(±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-methyl-pyrrolidin-3-yl]benzoate

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl) amino] pyrrolidin-3-yl]benzoate (20.0 mg, 44.8 umol, synthesized via Method 5, Steps 1-2 withacid A and amine AH as starting materials) in methanol (5 mL) was addedparaformaldehyde (14.3 mg, 448 umol) and acetic acid (2.69 mg, 44.8umol), and the mixture was stirred at rt for 0.5 hr. Then sodiumcyanoborohydride (28.1 mg, 448 umol) was added and the mixture wasstirred at rt for 5.5 hrs. On completion, the mixture was diluted withsaturated ammonium chloride (5 mL), extracted with dichloromethane (3×20mL) and the combined organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=10:1) to give the title compound. LCMS: (ES⁺)m:z (M+H)⁺=460.1, tR=0.737.

Step2—(±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-methyl-pyrrolidin-3-yl]benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-methyl-pyrrolidin-3-yl]benzoate(60.0 mg, 130 umol) in tetrahydrofuran (5 mL) and water (5 mL) was addedlithium hydroxide (3.12 mg, 389 umol), and the mixture was stirred at50° C. for 4 hrs. On completion, the reaction was concentrated to removethe tetrahydrofuran and the aqueous phase was acidified to pH=4-5 withhydrochloric acid (1 N). The product was extracted with dichloromethane(3×5 mL), and the combined organic phase was concentrated in vacuodirectly to give a residue which was purified by prep-HPLC (YMC-ActusODS-AQ 150*30 5 u, water (0.1% TFA)-ACN) and lyophilized in vacuo togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=446.1, tR=0.673. ¹H NMR(400 MHz, DMSO-d₆) δ=10.27 (br. s., 1H), 9.24 (br. s., 1H), 7.94 (d,J=8.0 Hz, 2H), 7.60 (d, J=7.3 Hz, 3H), 7.51-7.41 (m, 2H), 3.88 (s, 3H),2.94 (s, 3H), 2.92-2.80 (m, 2H), 2.56-2.53 (m, 2H), 2.40-2.36 (m, 2H).

Example18—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-ethyl-pyrrolidin-3-yl]benzoicacid

Step 1—(±)-Methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-ethyl-pyrrolidin-3-yl]benzoate

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoate(80.0 mg, 179 umol, synthesized via Method 5, Steps 1-2 with acid A andamine AH as starting materials) in dichloromethane (5 mL) was addedtriethylamine (181 mg, 1.79 mmol) and iodoethane (279 mg, 1.79 mmol) andthe mixture was stirred at rt for 2 hrs. On completion, the mixture wasdiluted with water (5 mL), extracted with ethyl acetate (3×5 mL) and thecombined organic phase was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a crude product. The crude waspurified by chromatography on silica gel (petroleum ether:ethylacetate=1:1 to dichloromethane:methanol=10:1) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=474.1, tR=0.735.

Step2—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-ethyl-pyrrolidin-3-yl]-benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-ethyl-pyrrolidin-3-yl]benzoate (60.0 mg, 126 umol) intetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (3.0mg, 126 umol), and the mixture was stirred at rt for 6 hrs. Oncompletion, the reaction was concentrated in vacuo to remove thetetrahydrofuran and the aqueous phase was acidified to pH=4-5 withhydrochloric acid (1 N). The product was extracted with dichloromethane(3×10 mL), and the combined organic phase was concentrated to give aresidue which was purified by prep-HPLC (Phenomenex Gemini C18 250*50mm*10 um, water (0.1% TFA)-ACN) to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=460.2, tR=0.721. ¹H NMR (400 MHz, DMSO-d₆) δ=10.07 (br. s.,1H), 9.10 (s, 1H), 7.96 (d, J=8.5 Hz, 2H), 7.63 (dd, J=8.0, 4.0 Hz, 3H),7.49-7.45 (m, 2H), 4.59 (d, J=8.0 Hz, 1H), 4.37 (d, J=6.0 Hz, 1H), 3.89(s, 3H), 3.85-3.68 (m, 2H), 3.10-2.81 (m, 2H), 2.46-2.37 (m, 2H),1.35-1.19 (m, 3H).

Example19—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]benzoicacid

Step 1—(±)-Methyl 4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(2,2,2-trifluoroethyl) pyrrolidin-3-yl]benzoate

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoate (70.0 mg, 156 umol synthesized via Method 5,Steps 1-2 with acid A and amine AH as starting materials) intetrahydrofuran (2 mL) was added diisopropylethylamine (337 mg, 2.61mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (54.6 mg, 235umol), and the mixture was stirred at rt for 12 hrs. On completion, themixture was diluted with water (10 mL) and extracted withdichloromethane (3×5 mL). The combined organic phase was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thecrude product. The crude product was purified by chromatography onsilica gel (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=30:1) to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=528.0, tR=1.123.

Step 2(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]benzoate (50.0 mg, 94.6umol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithiumhydroxide (2.27 mg, 94.6 umol) and the mixture was stirred at 60° C. for3 hrs. On completion, the reaction was concentrated to remove thetetrahydrofuran and the aqueous phase was acidified to pH=4-5 withhydrochloric acid (1N). The product was extracted with dichloromethane(2×10 mL), and the combined organic phase was concentrated in vacuo togive a crude product which was purified by prep-HPLC (Phenomenex GeminiC18 250*50 mm*10 um, water (0.1% TFA)-ACN) to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=514.1, tR=0.912. ¹H NMR (400 MHz, DMSO-d₆)δ=12.81 (br. s, 1H), 9.21 (br. s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.60 (d,J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.46-7.42 (m, 2H), 3.89 (s, 3H),3.59-3.59 (m, 2H), 3.32-3.30 (m, 1H), 3.09-3.06 (m, 1H), 2.96-2.88 (m,1H), 2.71-2.64 (m, 1H), 2.54-2.50 (m, 1H), 2.18-2.16 (m, 1H).

Example20—(±)-4-[1-Acetyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoicacid

Step 1—(±)-Methyl4-[1-acetyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoate

To a mixture of(±)-methyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-pyrrolidin-3-yl]-benzoate(100 mg, 224 umol, synthesized via Method 5, Steps 1-2 with acid A andamine AH as starting materials) and triethylamine (68.0 mg, 672 umol) indichloromethane (5 mL) was added acetyl chloride (26.4 mg, 336 umol)dropwise at 0° C. under nitrogen. The mixture was stirred at rt andstirred for 0.5 hour. On completion, the reaction was concentrated invacuo. The residue was purified by silica gel chromatography(dichloromethane:methanol=50:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ=9.24 (d, J=0.28 Hz, 1H), 7.96-7.93 (m, 2H), 7.64-7.57(m, 3H), 7.45-7.41 (m, 1H), 7.35 (s, 1H), 4.00-3.97 (m, 1H), 3.86 (d,J=0.36 Hz, 3H), 3.84 (d, J=0.16 Hz, 3H), 3.68-3.60 (m, 2H), 3.07-3.02(m, 1H), 2.40-2.28 (m, 1H), 2.00 (d, J=8.8 Hz, 3H), 1.90 (s, 1H).

Step2—(±)-4-[1-Acetyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoicacid

To a mixture of methyl-4-[1-acetyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-pyrrolidin-3-yl]-benzoate(100 mg, 133 umol) in tetrahydrofuran (3 mL) and water (3 mL) was addedlithium hydrate (47.8 mg, 2.00 mmol) in one portion at rt undernitrogen. The mixture was stirred at rt for 1 hour and then was warmedto 50° C. for 1 hour. On completion, the reaction was acidified by 2 Nhydrochloric acid (1 mL) to pH=2-3 and concentrated in vacuo. Theresidue was purified by prep-HPLC (Condition: 0.1% TFA-ACN; Column:Phenomenex Synergi C18 100*21.2 mm*4 um) to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=474.2, (M+H)⁺, tR=0.807. ¹H NMR (400 MHz,DMSO-d₆) δ=12.89 (s, 1H), 9.19 (d, J=0.20 Hz, 1H), 7.94-7.91 (m, 2H),7.64-7.57 (m, 3H), 7.54-7.40 (m, 1H), 7.33 (s, 1H), 4.24 (d, J=11.2 Hz,1H), 4.15 (dd, J=12.0 Hz, 1H), 3.87 (d, J=0.32 Hz, 3H), 3.66-3.54 (m,1H), 3.35-3.25 (m, 1H), 2.80-2.60 (m, 1H), 2.41-2.28 (m, 1H), 2.00 (d,J=8.4 Hz, 3H).

Example21—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-phenyl-pyrrolidin-3-yl]benzoicacid

Step1—(±)-Methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-phenyl-pyrrolidin-3-yl]benzoate

To a solution (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-3-yl]benzoate(70.0 mg, 156 umol, synthesized via Method 5, Steps 1-2 with acid A andamine AH as starting materials) and iodobenzene (159 mg, 784 umol) indioxane (5 mL) was added cesium carbonate (102 mg, 313 umol), RuPhos(36.5 mg, 78.4 umol) and Pd₂(dba)₃ (71.8 mg, 78.4 umol). The mixture wasstirred at 100° C. for 16 hrs under nitrogen. To the mixture was addedmethanol (10 mL), then the mixture was filtered. The filtrate wasconcentrated to give the crude product, which was purified by prep-TLC(petroleum ether:ethyl acetate=5:1) to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ=2.61 (dt, J=12.6, 7.8 Hz, 1H), 2.97-2.87 (m, 1H),3.51 (td, J=8.8, 4.0 Hz, 1H), 3.70-3.63 (m, 1H), 4.02-3.88 (m, 8H), 6.67(d, J=8.0 Hz, 2H), 6.79 (t, J=7.2 Hz, 1H), 6.83 (s, 1H), 7.02-6.97 (m,1H), 7.21 (d, J=8.8 Hz, 1H), 7.33-7.29 (m, 2H), 7.36 (d, J=8.8 Hz, 1H),7.58 (d, J=8.5 Hz, 2H), 8.11-8.00 (m, 2H).

Step2—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-phenyl-pyrrolidin-3-yl]benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1-phenyl-pyrrolidin-3-yl]benzoate(25.0 mg, 47.8 umol) in tetrahydrofuran (1 mL) and water (1 mL) wasadded lithium hydroxide (2.29 mg, 95.7 umol), then the mixture wasstirred at rt for 48 hrs. On completion, the reaction mixture wasconcentrated to remove the tetrahydrofuran and the aqueous phase wasacidified by HCl (2N, 0.1 mL) to pH=4-5, a white solid was precipitatedout. The mixture was filtered, and the filter cake was dissolved withacetonitrile and purified by prep-HPLC (condition: water (0.225% FA)—ACNcolumn: Boston Green ODS 150*30 5 u) and lyophilized to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=508.1, tR=0.946. ¹H NMR (400 MHz,DMSO-d₆) δ=2.45-2.40 (m, 1H), 2.93-2.89 (m, 1H), 3.93-3.81 (m, 5H),4.09-3.96 (m, 2H), 6.64-6.57 (m, 3H), 7.19 (t, J=7.8 Hz, 2H), 7.37 (s,1H), 7.43 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.8 Hz,1H), 7.89 (d, J=8.0 Hz, 2H), 9.24 (s, 1H).

Example 22 (Method6)—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]benzoicacid

Step 1—(±)-Methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]benzoate

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (250 mg,1.02 mmol) in a mixture of N,N-dimethylformamide (5 uL) anddichloromethane (30 mL) was added oxalyl chloride (195 mg, 1.54 mmol,134 uL) dropwise and the reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give4,5-dichloro-1-methyl-indole-2-carbonyl chloride (300 mg, crude) aswhite solid and for the next step directly. To a solution of (±)-methyl4-(3-aminooxetan-3-yl)benzoate (100 mg, 482 umol) and triethylamine (195mg, 1.93 mmol, 267 uL) in dichloromethane (20 mL) was added a solutionof 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (139 mg, 530 umol)in dichloromethane (10 mL) dropwise and the reaction mixture was stirredat rt for 0.5 hr. On completion, the reaction mixture was concentratedin vacuo. The resulting solid was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=433.0, tR=0.955. ¹H NMR (400 MHz, CDCl₃) δ=8.10 (d,J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.27-7.23(m, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 5.16 (d, J=7.0 Hz, 2H), 5.03 (d,J=6.9 Hz, 2H), 4.01 (s, 3H), 3.93 (s, 3H).

Step2—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]benzoate (100 mg, 230 umol) in a mixture oftetrahydrofuran (10 mL) and water (3 mL) was added lithium hydroxide(22.1 mg, 923 umol) and the reaction mixture was stirred at rt for 16hrs. On completion, the reaction mixture was acidified with 1Nhydrochloric acid solution until pH=6 and concentrated in vacuo toremove the tetrahydrofuran and water. The resulting solid was purifiedby prep-HPLC (Mobile phase: water (0.225% FA)-ACN, Column: Boston GreenODS 150*30 5 u) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=419.0, tR=0.842. ¹H NMR (400 MHz, DMSO-d₆) δ=9.83 (br. s, 1H),8.00 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.4 Hz, 1H),7.48 (d, J=8.9 Hz, 1H), 7.44 (s, 1H), 5.07 (d, J=6.9 Hz, 2H), 4.82 (d,J=6.9 Hz, 2H), 3.96 (s, 3H).

Method 6 Table: Compounds Synthesized via Method 6 using the appropriateacid and amine LCMS Ex- Inter- Inter- (ES+) ample mediate mediate m/zHNMR (400 MHz, # Structure Acid Amine (M + H)⁺ DMSO-d6) δ 23

  (±)-4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxan-3-yl]benzoicacid A AF 447.2 12.84 (br. s., 1H), 8.69 (s, 1H), 7.91 (d, J = 8.4 Hz,2H), 7.66-7.56 (m, 3H), 7.48-7.40 (m, 2H), 4.13 (d, J = 11.4 Hz, 1H),3.86 (s, 3H), 3.85-3.80 (m, 1H), 3.77 (d, J = 11.2 Hz, 1H), 3.56 (t, J =9.6 Hz, 1H), 2.68 (d, J = 12.8 Hz, 1H), 2.12 (t, J = 10.2 Hz, 1H), 1.84(d, J = 12.8 Hz, 1H), 1.50 (d, J = 13.6 Hz, 1H) 24

  (±)-3-chloro-4-[3-(4,5- dichloro-1-methyl-1H-indole-2-amido)oxolan-3-yl]benzoic acid A AJ 467.0 9.22 (s, 1H), 7.79 (d, J =1.3 Hz, 1H), 7.72 (dd, J = 1.5, 8.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H),7.52 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.35 (s, 1H), 4.53(d, J = 9.0 Hz, 1H), 4.23 (d, J = 9.3 Hz, 1H), 4.05- 3.92 (m, 1H), 3.91-3.87 (m, 1H), 3.86 (s, 3H), 3.08-2.96 (m, 1H), 2.48-2.39 (m, 1H). 25

  4-[4-(4,5-dichloro-1-methyl- 1H-indole-2-amido)oxan-4- yl]benzoic acidA AM 446.2 8.80 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.63- 7.55 (m, 3H),7.46 (d, J = 8.9 Hz, 1H), 7.40 (s, 1H), 3.86 (s, 3H), 3.84- 3.73 (m,4H), 2.56-2.52 (m, 2H), 2.07-1.97 (m, 2H) 26

  (±)-4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]benzoic acid B AN 429.1 9.21 (s, 1H), 7.91 (d, J =8.4 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 7.34(s, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.22 (q, J = 9.2 Hz, 2H), 3.99- 3.93(m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.83- 2.74 (m, 1H), 2.32 (td, J =8.0, 13.0 Hz, 1H) 27

  (±)-6-[3-(4,5-dichloro-1- methyl-1H-indole-2-amido)oxolan-3-yl]pyridine- 3-carboxylic acid A AT 434.2 13.28 (br. s.,1H), 9.34 (s, 1H), 9.03 (d, J = 1.5 Hz, 1H), 8.23 (d, 8.4 Hz, 1H),7.68-7.55 (m, 2H), 7.51-7.40 (m, 2H), 4.29 (d, J = 1.8 Hz, 2H), 4.00 (t,J = 6.9 Hz, 2H), 3.90 (s, 3H), 2.68-2.63 (m, 1H), 2.60-2.54 (m, 1H) 28

  (±)-5-[3-(4,5-dichloro-1- methyl-1H-indole-2-amido)oxolan-3-yl]pyridine- 2-carboxylic acid A AU 434.2 12.91 (br. s.,1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.09-7.96 (m, 2H), 7.60 (d, J = 9.0 Hz,1H), 7.50-7.41 (m, 2H), 4.24 (s, 2H), 3.99 (t, J = 7.0 Hz, 2H), 3.89 (s,3H), 2.841- 2.77 (m, 1H), 2.45- 2.39 (m, 1H) 29

  (±)-4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxolan-3-yl]-3-fluorobenzoic acid A AO 451.1 9.25 (s, 1H), 7.80- 7.71 (m, 1H), 7.69-7.52 (m, 3H), 7.43 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 4.46 (d, J = 9.0Hz, 1H), 4.14 (d, J = 9.2 Hz, 1H), 4.01- 3.90 (m, 2H), 3.87 (s, 3H),2.98-2.85 (m, 1H), 2.45-2.36 (m, 1H) 30

  (±)-4-[3-(4-chloro-1-methyl- 1H-indole-2-amido)oxolan-3- yl]benzoicacid C AN 399.2 9.17 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1Hz, 1H), 7.44- 7.36 (m, 3H), 7.32- 7.24 (m, 1H), 7.23- 7.14 (m, 1H),4.25 (d, J = 9.0 Hz, 1H, 1H), 4.15 (d, J = 9.0 Hz, 1H), 4.01-3.94 (m,2H), 3.90 (s, 3H), 2.87- 2.70 (m, 1H), 2.32 (td, J = 7.8, 13.0 Hz, 1H)31

  (±)-4-[3-(4-chloro-5- fluoro-1-methyl-1H- indole-2-amido)oxolan-3-yl]benzoic acid D AN 417.1 9.16 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.59(dd, J = 3.8, 9.0 Hz, 1H), 7.43 (s, 1H), 7.37- 7.28 (m, 3H), 4.28 (d, J= 9.0 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.99-3.93 (m, 2H), 3.91 (s,3H), 2.80 (td, J = 6.1, 12.6 Hz, 1H), 2.32 (td, J = 8.0, 12.8 Hz, 1H) 32

  (±)-4-[3-(4-chloro-1,5- dimethyl-1H-indole-2-amido)oxolan-3-yl]benzoic acid E AN 413.1 9.31-9.15 (s, 1H), 7.92 (d, J= 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.39(s, 1H), 7.29-7.19 (m, 1H), 4.29-4.16 (m, 2H), 4.02-3.93 (m, 2H), 3.88(s, 3H), 2.80 (td, J = 6.2, 12.7 Hz, 1H), 2.43 (s, 3H), 2.36- 2.28 (m,1H) 33

  (±)-4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]benzoic acid F AN 463.0 9.17 (s, 1H), 7.91 (d, J =8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.41 (s, 1H), 7.27 (s, 1H),4.27-4.16 (m, 2H), 3.99-3.91 (m, 5H), 3.90 (s, 3H), 2.78 (td, J = 6.1,12.6 Hz, 1H), 2.40-2.27 (m, 1H) 34

  (±)-4-[3-(4-chloro-6- methoxy-1-methyl-1H- indole-2-amido)oxolan-3-yl]benzoic acid G AN 429.1 12.83 (br s, 1H), 9.10 (s, 1H), 7.91 (d, J =8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 7.04 (s, 1H), 6.88(s, 1H), 4.21 (s, 2H), 3.96-3.93 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H),2.79-2.75 (m, 1H), 2.32-2.29 (m, 1H) 35

  (±)-4-(3-{9-chloro-6-methyl- 2H,3H,6H-[1,4]dioxino[2,3-f]indole-7-amido}oxolan-3- yl)benzoic acid J AN 457.2 9.09 (s, 1H), 7.90(d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H), 7.04 (s,1H), 4.33 (dd, J = 4.8, 14.3 Hz, 4H), 4.25-4.17 (m, 2H), 3.99-3.92 (m,2H), 3.79 (s, 3H), 2.78 (m, 1H), 2.33- 2.26 (m, 1H) 36

  (±)-4-[3-(4-chloro-5- cyclopropyl-1-methyl- 1H-indole-2-amido)oxolan-3- yl]benzoic acid L AN 439.1 12.86 (br. s., 1H), 9.22 (s,1H), 7.92 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.43 (d, J =8.8 Hz, 1H), 7.40 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.27-4.18 (m, 2H),4.01-3.93 (m, 2H), 3.87 (s, 3H), 2.83-2.77 (m, 1H), 2.35-2.21 (m, 2H),1.06-0.98 (m, 2H), 0.74-0.70 (m, 2H) 37

  (±)-2-{4-[3-(4,5-dichloro- 1-methyl-1H-indole-2- amido)oxolan-3-yl]phenyl}-2- methylpropanoic acid A AW 475.1 9.15 (s, 1H), 7.60 (d, J =8.8 Hz, 1H), 7.49- 7.42 (m, 2H), 7.42- 7.36 (m, 2H), 7.35- 7.26 (m, 2H),4.27 (d, J = 9.3 Hz, 1H), 4.11 (d, J = 9.0 Hz, 1H), 4.00- 3.93 (m, 2H),3.92 (s, 3H), 2.78 (td, J = 6.2, 12.7 Hz, 1H), 2.37- 2.29 (m, 1H), 1.46(s, 6H) 38

  (±)-1-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxolan-3-yl]phenyl}cyclopropane-1- carboxylic acid A AY 473.2 9.14 (s, 1H), 7.60(d, J = 8.9 Hz, 1H), 7.48- 7.41 (m, 2H), 7.35 (d, J = 8 Hz, 2H), 7.25(d, J = 8 Hz, 2H), 4.28 (d, J = 9.0 Hz, 1H), 4.11 (d, J = 9.0 Hz, 1H),3.98- 3.94 (m, 2H), 3.92 (s, 3H), 2.79 (td, J = 6.2, 12.6 Hz, 1H), 2.32(td, J = 8.0, 12.8 Hz, 1H) 1.35 (d, J = 2.1 Hz, 2H), 0.98 (d, J = 2.0Hz, 2H) 39

  2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}acetic acid B BA 429.1 9.64 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H),7.42 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 7.25-7.22 (m, 3H), 5.03 (d, J =6.4 Hz, 2H), 4.77 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.26(s, 2H) 40

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole- 2-amido)oxolan-3-yl]phenyl}acetic acid B AV 443.2 9.08 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H),7.37 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.23-7.18 (m, 3H), 4.26 (d, J =9.0 Hz, 1H), 4.12 (d, J = 9.0 Hz, 1H), 3.94 (t, J = 7.0 Hz, 2H), 3.90(s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.78 (td, J = 6.1, 12.6 Hz, 1H),2.37- 2.25 (m, 1H) 41

  4-[3-(4,5-dichloro-1-methyl- 1H-indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid A BB 437.1 9.93 (s, 1H), 7.81- 7.72 (m, 2H),7.68 (dd, J = 1.2, 11.6 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.45 (d, J =8.9 Hz, 1H), 7.39 (s, 1H), 5.11-5.07 (m, 2H), 5.07-5.03 (m, 2H), 3.92(s, 3H) 42

  4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]-3-fluorobenzoic acid F BB 467.0 9.73 (s, 1H), 7.70-7.72 (d, J = 8.4Hz, 1H), 7.58-7.61 (m, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 5.01-5.07 (m,4H), 3.94 (s, 3H), 3.91 (s, 3H) 43

  2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-fluorophenyl}acetic acid A BC 451.1 9.84 (s, 1H), 7.63- 7.60 (m, 2H),7.52 (t, J = 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.08~7.14 (m, 2H),5.02~5.06 (m, 4H), 3.94 (s, 3H), 3.53 (s, 2H) 44

  2-{4-[3-(4-chloro-1,5- dimethyl-1H-indole-2- amido)oxetan-3-yl]-3-fluorophenyl}acetic acid E BC 431.1 9.74 (s, 1H), 7.51 (t, J = 8.3 Hz,1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H),7.16-7.05 (m, 2H), 5.04 (s, 4H), 3.91 (s, 3H), 3.53 (s, 2H), 2.42 (s,3H) 45

  2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]-3-fluorophenyl}acetic acid F BC 479.1 9.69 (s, 1H), 7.50 (t, J = 8.0Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.08~7.13 (m, 2H), 5.01~5.05 (m,4H), 3.95 (s, 3H), 3.93 (s, 3H), 3.52 (s, 2H) 46

  2-{4-[3-(4-chloro-6-methoxy- 1,5-dimethyl-1H-indole-2-amido)oxetan-3-yl]-3- fluorophenyl}acetic acid M BC 461.0 9.58 (s, 1H),8.38 (br. s., 1H), 7.56-7.43 (m, 1H), 7.28 (s, 1H), 7.13- 7.05 (m, 2H),7.03 (s, 1H), 5.05-4.95 (m, 4H), 3.90 (s, 3H), 3.89 (s, 3H), 3.47 (s,2H), 2.28 (s, 3H) 47

  2-{4-[3-(4-chloro-5-fluoro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3- fluorophenyl}acetic acid N BC 465.0 9.66 (s,1H), 7.52 (t, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 6.7 Hz, 1H),7.13-7.08 (m, 2H), 4.98-5.08 (m, 4H), 3.94 (s, 3H), 3.92 (s, 3H), 3.58(s, 2H) 48

  3-chloro-4-[3-(4,5-dichloro-1- methyl-1H-indole-2-amido)oxetan-3-yl]benzoic acid A BD 453.0 9.96 (s, 1H), 7.93- 7.82 (m,3H), 7.59 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H),5.16 (d, J = 7.3 Hz, 2H), 5.10 (d, J = 7.3 Hz, 2H), 3.90 (s, 3H) 49

  2-{3-chloro-4-[3-(4,5- dichloro-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}acetic acid A BE 467.0 9.82 (s, 1H), 7.63- 7.52 (m, 2H), 7.43(d, J = 8.9 Hz, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 7.14 (d, J = 7.7 Hz,1H), 5.08 (m, 4H), 3.91 (s, 3H), 3.16 (s, 2H) 50

  4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-methylbenzoic acid A BF 433.2 9.83 (s, 1H), 7.72- 7.65 (m, 2H), 7.57 (d,J = 9.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H),7.32 (s, 1H), 5.17- 5.04 (m, 4H), 3.91 (s, 3H), 2.25 (s, 3H) 51

  2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-methylphenyl}acetic acid A BG 447.2 9.78 (s, 1H), 7.57 (d, J = 9.0 Hz,1H), 7.43 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H),7.01 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 5.14-5.01 (m, 4H), 3.92 (s, 3H),3.16 (s, 2H), 2.19 (s, 3H) 52

  2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-methoxyphenyl}acetic acid A BI 463.2 9.51 (s, 1H), 7.54 (d, J = 9.0 Hz,1H), 7.43- 7.35 (m, 2H), 7.32 (s, 1H), 6.90 (s, 1H), 6.81 (d, J = 7.6Hz, 1H), 5.05-4.96 (m, 4H), 3.89 (s, 3H), 3.79 (s, 3H), 3.41 (s, 2H) 53^(a)

  (±)-2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxolan-3-yl]-3-fluorophenyl}propanoic acid A BJ 478.9 9.12 (s, 1H), 7.58 (d, J = 9.0Hz, 1H), 7.47- 7.41 (m, 2H), 7.35 (s, 1H), 7.15-7.05 (m, 2H), 4.48 (d, J= 9.0 Hz, 1H), 4.06 (d, J = 9.3 Hz, 1H), 3.99- 3.92 (m, 3H), 3.90 (s,3H), 3.65-3.55 (m, 1H), 2.96-2.87 (m, 1H), 2.44-2.32 (m, 1H), 1.34 (d, J= 7.0 Hz, 3H)  54^(a)

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]-3- fluorophenyl}propanoic acid F BJ 509.0 8.99 (s,1H), 7.44 (t, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 7.12- 7.05(m, 2H), 4.47 (d, J = 8.8 Hz, 1H), 4.06 (d, J = 9.0 Hz, 1H), 3.95 (s,3H), 3.94- 3.91 (m, 1H), 3.89 (s, 3H), 3.72-3.67 (m, 1H), 2.90 (d, J =6.3 Hz, 1H), 2.49-2.34 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H)  55^(a)

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]-3- fluorophenyl}propanoic acid B BJ 475.1 9.03 (s,1H), 7.54- 7.37 (m, 2H), 7.28- 7.16 (m, 2H), 7.14- 7.02 (m, 2H), 4.48(d, J = 9.0 Hz, 1H), 4.07 (d, J = 9.0 Hz, 1H), 4.00- 3.89 (m, 2H), 3.89(s, 3H), 3.86 (s, 3H), 3.72- 3.65 (m, 1H), 2.97- 2.86 (m, 1H), 2.38 (td,J = 8.3, 13.1 Hz, 1H), 1.45-1.23 (m, 3H) 56

  (±)-2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxolan-3-yl]phenyl}butanoic acid A BL 497.2 (M + 23)⁺ 9.15 (s, 1H), 7.60 (d, J =8.9 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J = 5.9 Hz, 1H), 7.39 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.27 (d, J = 9.2 Hz, 1H), 4.11 (d, J= 9.2 Hz, 1H), 3.99-3.92 (m, 2H), 3.91 (s, 3H), 3.36 (d, J = 7.7 Hz,1H), 2.78 (td, J = 6.2, 12.7 Hz, 1H), 2.32 (td, J = 8.0, 12.9 Hz, 1H),2.04-1.87 (m, 1H), 1.63 (m, 13.9 Hz, 1H), 0.83 (t, J = 7.3 Hz, 3H) 57^(b)

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxolan-3-yl]phenyl}propanoic acid B BM 457.0 12.27 (br. s., 1H), 9.07 (s, 1H),7.50 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H),7.28-7.20 (m, 3H), 4.26 (d, J = 9.0 Hz, 1H), 4.12 (d, J = 9.3 Hz, 1H),3.94 (t, J = 6.9 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.64 (q, J = 7.0Hz, 1H), 2.78 (m, 1H), 2.34- 2.26 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H) 58

  (±)-2-{4-[3-(4,5-dichloro- 1-methyl-1H-indole-2- amido)oxetan-3-yl]phenyl}propanoic acid A BN 446.9 9.73 (s, 1H), 7.62 (d, J = 8.8 Hz,1H), 7.53- 7.45 (m, 3H), 7.42 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H), 5.04(d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.7 Hz, 2H), 3.97 (s, 3H), 3.58-3.43(m, 1H), 1.32 (d, J = 7.0 Hz, 3H) 59

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole- 2-amido)oxetan-3-yl]phenyl}propanoic acid B BN 443.0 9.64 (s, 1H), 7.58- 7.49 (m, 3H),7.37- 7.30 (m, 3H), 7.25 (d, J = 9.0 Hz, 1H), 5.04 (d, J = 6.7 Hz, 2H),4.78 (d, J = 6.7 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.63 (q, J = 6.7Hz, 1H), 1.35 (d, J = 7.2 Hz, 3H)  60^(c)

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3- fluorophenyl}propanoic acid B BO 461.1 9.75 (s,1H), 7.53- 7.49 (m, 2H), 7.28 (s, 1H), 7.23 (d, J = 9.2 Hz, 1H),7.16-7.12 (m, 2H), 5.06-4.97 (m, 4H), 3.91 (s, 3H), 3.88 (s, 3H), 3.62-3.61 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H)  61^(c)

  2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-fluorophenyl}propanoic acid A BO 465.0 9.83 (s, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (s,1H), 7.10- 7.14 (m, 2H), 5.01- 5.05 (m, 4H), 3.93 (s, 3H), 3.30-3.93 (m,1H), 1.30 (d, J = 7.2 Hz, 3H) 62

  2-{3-chloro-4-[3-(4,5- dichloro-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}propanoic acid A BQ 483.1 9.88 (s, 1H), 7.68 (d, J = 8.0 Hz,1H), 7.59 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.35-7.30 (m,2H), 7.29 (d, J = 8.0 Hz, 1H), 5.17-5.10 (m, 2H), 5.09-5.02 (m, 2H),3.92 (s, 3H), 3.77- 3.57 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H)  63^(d)

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}- 2-methylpropanoic acid B AW 471.2 9.07 (s,1H), 7.50 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.35- 7.29 (m,3H), 7.23 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 9.0 Hz, 1H), 4.12 (d, J =9.3 Hz, 1H), 3.94 (t, J = 7.0 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.79(td, J = 6.1, 12.6 Hz, 1H), 2.31 (td, J = 7.8, 13.0 Hz, 1H), 1.46 (s,6H) 64

  2-{3-chloro-4-[3-(4- chloro-5-methoxy-1- methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}acetic acid B BW 463.2 9.78 (s, 1H), 7.67 (d,J = 8.0 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.34 (s, 1H), 7.29-7.16 (m,3H), 5.28-4.77 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.58 (s, 2H) 65

  4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid B BF 429.1 9.67 (s, 1H), 7.69- 7.62 (m, 2H),7.50- 7.46 (m, 2H), 7.21- 7.17 (m, 2H), 5.11- 5.03 (m, 4H), 3.88 (s,3H), 3.86 (s, 3H),, 2.23 (s, 3H) 66

  4-[3-(4-chloro-5-methoxy-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-fluorobenzoic acid B BB 433.3 9.76 (s, 1H), 7.67-7.69 (d, J = 8 Hz, 1H),7.54- 7.58 (m, 2H), 7.78-7.51 (d, J = 12 Hz, 1H), 7.28 (s, 1H),7.21-7.23 (d, J = 8 Hz, 1H), 5.02- 5.07 (m, 4H), 3.89 (s, 3H), 3.87 (s,3H) 67

  3-chloro-4-[3-(4,5-dichloro- 6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]benzoic acid F BD 485.0 9.79 (s, 1H), 7.92-7.84 (m, 2H), 7.82- 7.74 (m, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 5.20- 5.11(d, J = 7.0 Hz, 2H), 5.08 (d, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.90 (s,3H) 68

  4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]-3-methylbenzoic acid F BF 462.9 9.57 (s, 1H), 7.71- 7.63 (m, 2H),7.49 (d, J = 7.6 Hz, 1H), 7.27- 7.19 (m, 2H), 5.12 (d, J = 6.8 Hz, 2H),5.06 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.24 (s, 3H) 69

  3-chloro-4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]benzoic acid B BD 449.1 9.88 (s, 1H), 7.95- 7.83 (m,3H), 7.49 (d, J = 9.0 Hz, 1H), 7.29- 7.18 (m, 2H), 5.18-5.13 (d, J = 8.0Hz, 2H), 5.12-5.07 (d, J = 7.6 Hz, 2H), 3.87 (s, 3H), 3.87 (s, 3H) 70^(e)

  (±)-1-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxolan-3-yl]phenyl}cyclopropane- 1-carboxylic acid B AY 469.3 9.04 (s, 1H), 7.50(d, J = 9.0 Hz, 1H), 7.32 (s, 1H), 7.30-7.26 (m, 2H), 7.25-7.20 (m, 3H),4.28 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.97- 3.91 (m, 2H),3.89 (s, 3H), 3.88 (s, 3H), 2.79 (td, J = 6.2, 12.6 Hz, 1H), 2.30 (td, J= 8.0, 12.9 Hz, 1H), 1.26 (d, J = 2.4 Hz, 2H), 0.82 (d, J = 2.0 Hz, 2H)71

  2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}propanoic acid F BN 477.1 9.61 (s, 1H), 7.54 (d, J = 8.3 Hz,2H), 7.39- 7.26 (m, 4H), 5.04 (d, J = 6.8 Hz, 2H), 4.78 (d, J = 6.5 Hz,2H), 3.96 (s, 3H), 3.95 (s, 3H), 3.67 (q, J = 7.0 Hz, 1H), 1.36 (d, J =7.3 Hz, 3H) 72

  2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}-5- hydroxypentanoic acid B CD 487.2 9.65 (s, 1H), 7.53 (d, J= 9.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33- 7.27 (m, 3H), 7.24 (d, J= 9.2 Hz, 1H), 5.03 (d, J = 6.7 Hz, 2H), 4.77 (d, J = 6.5 Hz, 2H), 3.93(s, 3H), 3.89 (s, 3H), 3.36 (t, J = 6.4 Hz, 2H), 3.26 (t, J = 6.3 Hz,1H), 2.00- 1.87 (m, 1H), 1.62-1.50 (m, 1H), 1.47-1.24 (m, 2H) 73

  3-chloro-4-[3-(4-chloro-6- methoxy-1,5-dimethyl-1H-indole-2-amido)oxetan-3- yl]benzoic acid M BD 463.2 9.69 (s, 1H), 7.92-7.84 (m, 2H), 7.77 (d, J = 12 Hz, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 5.15(d, J = 7.2 Hz, 2H), 5.08 (d, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.87 (s,3H), 2.27 (s, 3H) 74

  4-[3-(4-chloro-6-methoxy- 1,5-dimethyl-1H-indole-2-amido)oxetan-3-yl]-3- methylbenzoic acid M BF 443.1 9.57 (s, 1H), 7.69-7.66 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.01 (s, 1H), 5.11(d, J = 7.2 Hz, 2H), 5.06 (d, J = 6.8 Hz, 2H), 3.87 (s, 3H), 3.86 (s,3H), 2.26 (s, 3H), 2.24 (s, 3H) 75

  4-[3-(4-chloro-6-methoxy- 1,5-dimethyl-1H-indole-2-amido)oxetan-3-yl]-3- fluorobenzoic acid M BB 447.1 9.66 (s, 1H), 7.73(d, J = 8.0 Hz, 1H), 7.65- 7.60 (m, 2H), 7.30 (s, 1H), 7.03 (s, 1H),5.08- 5.02 (m, 4H), 3.90 (s, 3H), 3.89 (s, 3H), 2.27 (s, 3H) 76

  3-chloro-4-[3-(4-chloro-5- fluoro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]benzoic acid N BD 467.1 9.75 (s, 1H),7.89- 7.80 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J =6.5 Hz, 1H), 5.15 (d, J = 1.2 Hz, 2H), 5.08 (d, J = 7.2 Hz, 2H), 3.94(s, 3H), 3.90 (s, 3H) 77

  4-[3-(4-chloro-5-fluoro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]-3- methylbenzoic acid N BF 447.1 9.63 (s, 1H), 7.68(m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.26 (d, J = 6.8 Hz,1H), 5.12 (d, J = 7.2 Hz, 2H), 5.06 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H),3.89 (s, 3H), 2.23 (s, 3H) 78

  4-[3-(4-chloro-5-fluoro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]-3-fluorobenzoic acid N BB 449.0 9.75 (s,1H), 7.78- 7.67 (m, 3H), 7.36 (s, 1H), 7.27 (d, J = 6.8 Hz, 1H), 5.09(d, J = 7.0 Hz, 2H), 5.04 (d, J = 7.0 Hz, 2H), 3.94 (s, 3H), 3.91 (s,3H)  79^(f)

  (±)-2-{4-[3-(4,5-dichloro- 1-methyl-1H-indole-2- amido)oxolan-3-yl]-3-fluorophenyl}-2- methylpropanoic acid A BK 495.2 9.13 (s, 1H), 7.57 (d,J = 8.8 Hz, 1H), 7.49- 7.40 (m, 2H), 7.34 (s, 1H), 7.17-7.08 (m, 2H),4.47 (d, J = 9.0 Hz, 1H), 4.07 (d, J = 9.0 Hz, 1H), 4.00- 3.91 (m, 2H),3.89 (s, 3H), 2.95-2.87 (m, 1H), 2.43-2.34 (m, 1H), 1.46 (s, 6H)  80^(f)

  (±)-2-{4-[3-(4,5-dichloro- 6-methoxy-1-methyl-1H-indole-2-amido)oxolan-3- yl]-3-fluorophenyl}-2- methylpropanoic acid FBK 522.9 8.98 (s, 1H), 7.44 (t, J = 8.7 Hz, 1H), 7.30 (s, 1H), 7.24 (s,1H), 7.16- 7.07 (m, 2H), 4.47 (d, J = 9.0 Hz, 1H), 4.06 (d, J = 9.0 Hz,1H), 3.94 (s, 3H), 3.93- 3.90 (m, 2H), 3.89 (s, 3H), 2.94-2.87 (m, 1H),2.42-2.35 (m, 1H), 1.45 (s, 6H)  81^(f)

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxolan-3-yl]-3-fluorophenyl}-2- methylpropanoic acid B BK 489.2 9.04 (s, 1H),7.54- 7.39 (m, 2H), 7.29- 7.18 (m, 2H), 7.17- 7.05 (m, 2H), 4.47 (d, J =8.8 Hz, 1H), 4.07 (d, J = 9.3 Hz, 1H), 4.00- 3.90 (m, 2H), 3.87 (s, 3H),3.86 (s, 3H), 2.97- 2.86 (m, 1H), 2.42- 2.32 (m, 1H), 1.46 (s, 6H) 82

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxolan-3- yl]phenyl}butanoic acid F BL 505.0 12.3 (brs,1H), 9.03 (s, 1H), 7.42-7.34 (m, 3H), 7.27-7.17 (m, 3H), 4.26 (d, J =9.2 Hz, 1H), 4.12 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 3.95-3.92 (m, 2H),3.91 (s, 3H), 3.43- 3.40 (m, 1H), 2.78 (td, J = 6.1, 12.6 Hz, 1H), 2.31(td, J = 7.7, 13.0 Hz, 1H), 1.96 (quind, J = 7.2, 14.2 Hz, 1H), 1.64(quind, J = 7.0, 13.9 Hz, 1H), 0.84 (t, J = 7.3 Hz, 3H)  83^(g)

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxolan-3-yl]phenyl}- 3-methylbutanoic acid F CF 519.3 9.01 (s,1H), 7.41- 7.32 (m, 3H), 7.29- 7.24 (m, 3H), 4.26 (d, J = 8.5 Hz, 1H),4.11 (d, J = 9.3 Hz, 1H), 3.96 (s, 3H), 3.95-3.92 (m, 1H), 3.91 (s, 3H),3.03 (d, J = 10.3 Hz, 1H), 2.78 (td, J = 6.2, 12.5 Hz, 1H), 2.57-2.53(m, 1H), 2.38-2.25 (m, 1H), 2.24-2.05 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H),0.62 (d, J = 6.5 Hz, 3H) 84

  (±)-2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxolan-3-yl]phenyl}pentanoic acid A CG 489.2 9.10 (s, 1H), 7.58 (d, J = 8.8 Hz,1H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H),7.20 (d, J = 8.4 Hz, 2H), 4.26 (d, J = 9.0 Hz, 1H), 4.07 (d, J = 9.0 Hz,1H), 4.00- 3.91 (m, 2H), 3.90 (s, 3H), 3.23-3.19 (m, 1H), 2.77 (td, J =12.6, 6.1 Hz, 1H), 2.31- 2.24 (m, 1H), 1.92- 1.83 (m, 1H), 1.46 (qd, J =15.8, 6.4 Hz, 1H), 1.28-1.19 (m, 1H), 1.19-1.11 (m, 1H), 0.82 (t, J =7.4 Hz, 3H)  85^(h)

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxolan-3- yl]phenyl}pentanoic acid F CG 519.2 8.98 (s, 1H), 7.36(s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.28-7.18 (m, 3H), 4.26 (d, J = 9.0Hz, 1H), 4.09 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.94-3.91 (m, 2H), 3.90(s, 3H), 3.30- 3.25 (m, 1H), 2.76 (td, J = 12.4, 6.2 Hz, 1H), 2.32-2.23(m, 1H), 1.95-1.83 (m, 1H), 1.55-1.44 (m, 1H), 1.28-1.20 (m, 1H),1.20-1.13 (m, 1H), 0.84 (t, J = 7.4 Hz, 3H) 86

  (±)-2-cyclobutyl-2-{4-[3-(4,5- dichloro-1-methyl-1H-indole-2-amido)oxolan-3- yl]phenyl}acetic acid A CH 501.1 9.14 (s, 1H), 7.60(d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H) 7.34 (d, J =8.2 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 4.26 (d, J = 9.2 Hz, 1H), 4.08(d, J = 9.3 Hz, 1H), 3.98- 3.92 (m, 2H), 3.91 (s, 3H), 2.92-2.81 (m,1H), 2.81-2.73 (m, 1H), 2.54-2.52 (m, 1H), 2.36-2.30 (m, 1H), 2.08 (d, J= 5.0 Hz, 1H), 1.77-7.65 (m, 4H), 1.58-1.43 (m, 1H)  87^(i)

  (±)-2-cyclopentyl-2-{4-[3- (4,5-dichloro-1-methyl-1H-indole-2-amido)oxolan-3- yl]phenyl}acetic acid A CI 537.1 (M + Na)⁺12.21 (br. s., 1H), 9.13 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.45 (d, J =8.8 Hz, 1H), 7.42 (s, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3Hz,, 2H), 4.26 (d, J = 9.0 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.98- 3.92(m, 2H), 3.91 (s, 3H), 3.20 (d, J = 11.0 Hz, 1H), 2.78 (td, J = 6.1,12.6 Hz, 1H), 2.45- 2.39 (m, 1H), 2.33- 2.27 (m, 1H), 1.89- 1.77 (m,1H), 1.65- 1.47 (m, 3H), 1.46- 1.38 (m, 1H), 1.31- 1.18 (m, 2H), 1.00-0.88 (m, 1H)  88^(j)

  4-chloro-N-{3-[4- (acetamidosulfonyl)phenyl] oxetan-3-yl}-5-methoxy-1-methyl-1H-indole-2- carboxamide B BY 490.0 (M − 1)⁺ 9.74 (br, s, 1H),7.87 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.8 Hz,1H), 7.34 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 5.06 (d, J = 12 Hz, 2H),4.80 (d, J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.81 (s, 3H)^(a)Since Intermediate BJ was isolated as a mixture with IntermediateBK, the reaction formed a mixture of isomers which was separated afterStep 2. In Step 2, the gem di-methyl compound was not hydrolyzed and wasremoved during the aqueous work-up. ^(b)Step 2 run at 60° C. for 5 hrs.^(c)Since Intermediate BO was a mixture with Intermediate BP, themixture of products was purified after the first step. ^(d)Step 2 run at50-60° C. for 6 hrs. ^(e)Step 2 was heated at 60° C. for 2 hrs.^(f)Since Intermediate BK was isolated as a mixture with IntermediateBJ, the reaction formed a mixture of isomers which was separated afterStep 2. This gem-dimethyl product did not react at rt, and thus washeated further to 60° C. for 6 hr to complete the hydrolysis and formthe final product. ^(g)Step 2 was heated at 80° C. for 32 hrs. ^(h)Step2 was heated to 60° C. for 48 hrs. ^(i)Step 2 was run at 90° C. for 9hrs. ^(j)Only Step 1 was performed. No hydrolysis with LiOH.

Example 89—(±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-3-methyl-benzoicacid

Step 1—(±)-Methyl 4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-3-methyl-benzoate

A mixture of methyl3-bromo-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate(150 mg, 285 umol, synthesized via Method 6, Step 1 with acid A andamine AK as starting materials), 2, 4, 6-trimethyl-1, 3, 5, 2, 4,6-trioxatriborinane (35.7 mg, 285 umol), cesium carbonate (185 mg, 570umol) and Pd(dppf)Cl₂—CH₂Cl₂ (46.5 mg, 57.0 umol) in water (1 mL) anddioxane (5 mL) was degassed and purged with nitrogen gas for 3 times.Then the mixture was stirred at 100° C. for 16 hours under nitrogen gasatmosphere. On completion, the reaction mixture was concentrated invacuo to give a residue. The residue was purified by columnchromatography (SiO₂, dichloromethane:ethyl acetate=10:0 to 10:1) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=461.2, tR=0.950.

Step 2—(±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-3-methyl-benzoicacid

To a solution of methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-3-methyl-benzoate(60 mg, 130 umol) in water (1 mL) and tetrahydrofuran (3 mL) was addedlithium hydroxide (12.4 mg, 520 umol). The mixture was stirred at 60° C.for 16 hours. On completion, the reaction mixture was concentrated invacuo. The residue was acidified with 1 M hydrochloric acid to pH=3.Then the mixture was concentrated in vacuo to get the crude product. Thecrude product was purified by prep-HPLC (Condition: water (0.1%TFA)-ACN; Column: Venusil XBP C18 150*25 mm; Particle size: 10 um) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=447.2, tR=0.916. ¹H NMR(400 MHz, DMSO-d₆) δ=12.80 (br. s., 1H), 9.19 (s, 1H), 7.77-7.68 (m,2H), 7.61-7.52 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 4.44 (d,J=9.0 Hz, 1H), 4.23 (d, J=8.9 Hz, 1H), 3.97 (q, J=7.8 Hz, 2H), 3.86 (s,3H), 3.01-2.92 (m, 1H), 2.39 (s, 3H), 2.35-2.29 (m, 1H).

Example90—(±)-4,5-Dichloro-N-(3-(4-(cyanomethyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-N-[3-[4-(cyanomethyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(84.0 mg, 196 umol, synthesized via Step 1 of Method 6 with acid A andamine AX) in N,N-dimethylformamide (5 mL) was added sodium azide (63.7mg, 980 umol) and ammonium chloride (31.5 mg, 588 umol). The reactionmixture was stirred at 120° C. for 12 hrs. On completion, the mixturewas diluted with water (20 mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine (20 mL), driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by Prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini150*25 mm*10 um; Condition: water (0.05% ammonia hydroxide v/v)-ACN] togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=471.1, tR=0.831. ¹H NMR(400 MHz, DMSO-d₆) δ=9.17 (s, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.45 (d,J=8.8 Hz, 1H), 7.43-7.36 (m, 3H), 7.22 (d, J=8.0 Hz, 2H), 4.24 (d, J=9.0Hz, 1H), 4.21 (s, 2H), 4.10 (d, J=9.3 Hz, 1H), 3.96-3.92 (m, 2H), 3.90(s, 3H), 2.77 (td, J=6.1, 12.8 Hz, 1H), 2.32-2.23 (m, 1H).

Example91—(±)-N-(3-(4-(1-(1H-tetrazol-5-yl)ethyl)phenyl)tetrahydrofuran-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-N-[3-[4-(1-cyanoethyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(90.0 mg, 203 umol, synthesized via Method 6, Step 1 with acid A andamine BS) in N,N-dimethylformamide (5 mL) was added sodium azide (66.1mg, 1.02 mmol) and ammonium chloride (32.7 mg, 610 umol) under nitrogen.The reaction mixture was stirred at 120° C. for 12 hrs. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layer was washed with saturated brine(20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by prep-HPLC [Instrument: GX-h; Column: BostonpH-lex 150*25 10 um; Condition: water (0.05% ammonia hydroxide v/v)-ACN]to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=485.2, tR=0.861. ¹HNMR (400 MHz, DMSO-d₆) δ=9.13 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.44 (d,J=8.8 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.2 Hz,2H), 4.31 (q, J=7.2 Hz, 1H), 4.25 (d, J=9.0 Hz, 1H), 4.08 (dd, J=9.0,3.6 Hz, 1H), 3.96-3.91 (m, 2H), 3.90 (s, 3H), 2.76 (td, J=12.6, 6.2 Hz,1H), 2.32-2.24 (m, 1H), 1.56 (d, J=7.0 Hz, 3H).

Example92-4,5-Dichloro-1-methyl-N-[3-[4-(1H-tetrazol-5-ylmethyl)phenyl]oxetan-3-yl]indole-2-carboxamide

To a solution of4,5-dichloro-N-[3-[4-(cyanomethyl)phenyl]oxetan-3-yl]-1-methyl-indole-2-carboxamide(100 mg, 241 umol, synthesized via Method 6 with acid A and amine BX) inN,N-dimethylformamide (5 mL) was added NaN₃ (125 mg, 1.93 mmol) andammonium chloride (38.7 mg, 724 umol) under a nitrogen atmosphere. Thereaction mixture was stirred at 120° C. for 20 hrs. On completion, water(20 mL) was added into the reaction mixture, and the mixture wascarefully acidified to pH=6 with 0.5 N hydrochloric acid. The mixturewas extracted with ethyl acetate (2×30 mL) and the aqueous layer wasquenched with sodium hypochlorite solution and basified to pH=12 anddiscarded. The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a residue. Theresidue was purified with prep-HPLC (Instrument: GX-D; Column: BostonGreen ODS 150*30 5 u; Mobile phase: 0.225% formic acid-acetonitrile) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=457.1, tR=0.830. ¹H NMR(400 MHz, DMSO-d₆) δ=9.73 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.53 (d,J=8.2 Hz, 2H), 7.47 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J=8.0 Hz,2H), 5.04 (d, J=6.7 Hz, 2H), 4.78 (d, J=6.7 Hz, 2H), 4.22 (s, 2H), 3.96(s, 3H).

Example93—N-(3-(4-(N-Acetylsulfamoyl)phenyl)oxetan-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (140 mg,574 umol) in dichloromethane (5.00 mL) was added N,N-dimethylformamide(4.19 mg, 57.4 umol) and oxalyl dichloride (364 mg, 2.87 mmol) at rt.The mixture was stirred at rt for 2 hrs. On completion, the mixture wasconcentrated in vacuo to give a crude yellow solid (152 mg) which wasused in next step without any purification.

To a solution of N-[4-(3-aminooxetan-3-yl)phenyl]sulfonylacetamide (90.0mg, 333 umol) and diisopropyethylamine (129 mg, 999 umol) indichloromethane (5.00 mL) was added the solution of4,5-dichloro-1-methyl-indole-2-carbonyl chloride (105 mg, 400 umol) indichloromethane (5.00 mL) dropwise at rt. The mixture was stirred at rtfor 16 hrs. On completion, the solution was quenched with citric acidsolution (1M, 5 mL) and extracted with dichloromethane (10 mL). Theorganic phase was dried over sodium sulfate and concentrated in vacuo togive a residue which was purified by prep-HPLC (Condition: water (0.05%ammonia hydroxide v/v)-ACN; Column: Agela DuraShell 150 mm_25 mm_5 um)to give the title compound. LCMS: (ES⁺) m/z (M−H)⁺=494.0, tR=1.312. ¹HNMR (400 MHz, DMSO-d6) δ=9.81 (br, s, 1H), 7.81 (d, J=8.4 Hz, 2H),7.67-7.63 (m, 3H), 7.48 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 5.06 (d, J=6.8Hz, 2H), 4.81 (d, J=6.8 Hz, 2H), 3.97 (s, 3H), 1.72 (s, 3H).

Example94—(±)-2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydro-furan-3-yl)phenyl)-3-methylbutanoic acid

To a mixture of(±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]-3-methyl-butanoate(156 mg, 301 umol, synthesized via Method 6, Step 1 with acid A andamine CF) in anhydrous tetrahydrofuran (6 mL) and water (3 mL) was addedlithium hydroxide (36.1 mg, 1.51 mmol). Then the mixture was stirred at80° C. for 32 hours. On completion, the mixture was adjusted to pH=4-5with 1N hydrochloric acid, and the reaction mixture was concentrated invacuo to give a residue. The residue was purified by pre-HPLC(Instrument: GX-F; Condition: water (0.225% FA)-ACN; Column: PhenomenexSynergi C18 150*25*10 um) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=489.3, tR=0.969. ¹H NMR (400 MHz, DMSO-d₆) δ=9.15 (s, 1H), 7.60(d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J=8.0Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 4.27 (d, J=9.3 Hz, 1H), 4.10 (d, J=9.3Hz, 1H), 3.95 (t, J=7.4 Hz, 2H), 3.91 (s, 3H), 3.03 (d, J=10.3 Hz, 1H),2.78 (td, J=6.1, 12.6 Hz, 1H), 2.53-2.53 (m, 1H), 2.33-2.28 (m, 1H),0.99 (d, J=6.3 Hz, 3H), 0.62 (d, J=6.5 Hz, 3H).

Example 95 (Method7)—(±)-4-[3-[[4,5-Dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoicacid

Step 1—(±)-Ethyl4-[3-[(4,5-dichloro-6-hydroxy-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-benzoate

To a solution of 4,5-dichloro-6-hydroxy-1-methyl-indole-2-carboxylicacid (100 mg, 384 umol), HATU (160 mg, 423 umol) and triethylamine (117mg, 1.15 mmol) in N,N-dimethylformamide (5 mL) was added (±)-ethyl4-(3-aminotetrahydrofuran-3-yl)benzoate (90.4 mg, 388 umol) at 0° C.under nitrogen. The mixture was stirred at rt for 16 hours. Oncompletion, to the mixture was added water (20 mL), then the mixture wasadjusted to pH=4-5 with hydrochloric acid (2 N), and filtered to get thefilter cake. The filter cake was dried in vacuo to obtain the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=477.0, tR=0.878. ¹H NMR (300 MHz,DMSO-d6) δ=9.14 (s, 1H), 7.62-7.50 (m, 4H), 7.35 (s, 1H), 6.95 (s, 1H),4.30 (q, J=7.03 Hz, 4H), 4.07-3.98 (m, 2H), 3.77 (s, 3H), 2.77 (d,J=7.16 Hz, 1H), 2.28 (br. s., 1H), 1.26-1.08 (m, 3H).

Step 2—(±)-Ethyl4-[3-[[4,5-dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoate

To a solution of (±)-ethyl4-[3-[(4,5-dichloro-6-hydroxy-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate(140 mg, 293 umol) in N,N-dimethylformamide (5 mL) was added potassiumcarbonate (81.0 mg, 586 umol) and 5-(chloromethyl)oxazolidin-2-one (59.6mg, 439 umol, CAS #22625-57-6). Then the mixture was stirred at 100-110°C. for 16 hours. On completion, the mixture was cooled to roomtemperature and water (20 mL) was added. Then the mixture was extractedwith ethyl acetate (3×20 mL) and the combined phase was concentrated toobtain the crude product. The residue was purified by prep-TLC(petroleum ether:ethyl acetate=5:1 to 0:1) to obtain the title compound.¹H NMR (400 MHz, DMSO-d6) δ=9.20 (s, 1H), 7.96 (s, 2H), 7.65 (s, 1H),7.58 (d, J=8.53 Hz, 2H), 7.38 (d, J=15.81 Hz, 2H), 5.03-4.96 (m, 1H),4.38-4.27 (m, 4H), 4.21 (s, 2H), 3.99-3.93 (m, 2H), 3.88 (s, 3H),3.68-3.63 (m, 1H), 3.44 (br. s., 1H), 2.83-2.76 (m, 1H), 2.36-2.29 (m,1H), 1.31 (t, J=7.09 Hz, 3H).

Step3—(±)-4-[3-[[4,5-Dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoicacid

To a solution of (±)-ethyl4-[3-[[4,5-dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoate (80.0 mg, 138 umol) in tetrahydrofuran (2 mL) and water (2 mL)was added lithium hydroxide (6.65 mg, 277 umol) at rt, then the mixturewas stirred at rt for 16 hours. On completion, the mixture was adjustedto pH=4-5 with hydrochloric acid (2 N) and concentrated. The residue waspurified by prep-HPLC (condition: water (0.225%₀FA)-ACN; column: BostonGreen ODS 150*30 5 u) to give the title compound. ¹H NMR (400 MHz,DMSO-d6) δ=9.16 (s, 1H), 7.89 (d, J=8.41 Hz, 2H), 7.64 (s, 1H), 7.51 (d,J=8.41 Hz, 2H), 7.37 (d, J=16.56 Hz, 2H), 5.02-4.94 (m, 1H), 4.38-4.32(m, 1H), 4.32-4.25 (m, 1H), 4.24-4.14 (m, 2H), 3.99-3.91 (m, 2H), 3.87(s, 3H), 3.65 (t, J=9.03 Hz, 1H), 3.43-3.40 (m, 1H), 2.81-2.72 (m, 1H),2.32-2.26 (m, 1H).

Method 7 Table: Compounds Synthesized via Method 7 using the appropriateamine Ex- LCMS am- Inter- (ES+) ple mediate m/z HNMR (400 MHz, DMSO-d6)# Structure Amine (M + H)⁺ δ 96

  (±)-4-(3-{4-chloro-1-methyl-6- [(2-oxo-1,3-oxazolidin-5-yl)methoxy]-1H-indole-2- amido}oxolan-3-yl)benzoic acid 5-(chloromethyl) oxazolidin- 2-one 514.2 12.82 (br s, 1H), 9.12 (s, 1H),7.91 (d, J = 8.8 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.37(s, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 4.94 (t, J = 0.28 Hz, 1H),4.27-4.24 (m, 1H), 4.21 (s, 3H), 3.96 (d, J = 4.0 Hz, 2H), 3.85 (s, 3H),3.63 (t, J = 0.28 Hz, 1H), 3.36-3.32 (m, 1H), 2.78-2.75 (m, 1H), 2.49-2.29 (m, 1H) 97

  (±)-4-[3-(4,5-dichloro-6- ethoxy-1-methyl-1H- indole-2-amido)oxolan-3-yl]benzoic acid EtI 477.0 9.15 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.53(d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.26 (s, 1H), 4.27-4.16 (m, 4H),4.02-3.92 (m, 2H), 3.88 (s, 3H), 2.83- 2.74 (m, 1H), 2.33-2.27 (m, 1H),1.42 (t, J = 6.8 Hz, 3H) 98

  (±)-4-{3-[4,5-dichloro-1- methyl-6-(oxolan-2- ylmethoxy)-1H-indole-2-amido]oxolan-3-yl}benzoic acid 2- (bromomethyl)- tetrahydro- furan 533.19.12 (s, 1H), 8.34 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 7.38 (s, 1H), 7.29 (s, 1H), 4.22-4.24 (m, 2H), 4.16-4.18 (m,1H), 4.13- 4.14 (m, 1H), 3.95-3.97 (m, 2H), 3.87 (s, 3H), 3.70-3.72 (m,2H), 2.74-2.81 (m, 2H), 1.95-2.05 (m, 2H), 1.74-1.87 (m, 2H) 99

  (±)-4-{3-[4,5-dichloro-6- (2-methoxyethoxy)-1- methyl-1H-indole-2-amido]oxolan-3-yl}benzoic acid 1-chloro- 2- methoxy- ethane 507.1 12.84(br. s., 1H), 9.16 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3Hz, 2H), 7.39 (s, 1H), 7.29 (s, 1H), 4.32-4.26 (m, 2H), 4.24-4.16 (m,2H), 3.99-3.92 (m, 2H), 3.87 (s, 3H), 3.77-3.71 (m, 2H), 3.36 (s, 3H),2.77 (t, J = 12.6, 1H), 2.34-2.25 (m, 1H) 100

  (±)-4-(3-{4,5-dichloro-1- methyl-6-[(1-methyl-5- oxopyrrolidin-3-yl)methoxy]-1H-indole-2- amido}oxolan-3-yl)benzoic acid AQ 560.012.96-12.73 (br. s., 1H), 9.18 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.55(d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 7.33 (s, 1H), 4.21 (d, J = 3.5 Hz,2H), 4.15-4.13 (m, 2H), 3.98-3.96 (m, 2H), 3.88 (s, 3H), 3.57 (s, 2H),3.29- 3.26 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.76 (m, 1H), 2.74 (s, 3H),2.30-2.13 (m, 2H) 101

  (±)-4-{3-[4,5-dichloro-1- methyl-6-(oxolan-3- ylmethoxy)-1H-indole-2-amido]oxolan-3-yl}benzoic acid AR 533.3 12.86 (br. s., 1H), 9.17 (s,1H), 7.92 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.40 (s, 1H),7.31 (s, 1H), 4.25-4.17 (m, 2H), 4.16-4.10 (m, 1H), 4.09-4.03 (m, 1H),3.99-3.93 (m, 2H), 3.88 (s, 3H), 3.84- 3.77 (m, 2H), 3.73-3.66 (m, 1H),3.61 (dd, J = 5.5, 8.6 Hz, 1H), 2.81-2.70 (m, 2H), 2.32 (td, J = 7.9,12.9 Hz, 1H), 2.11- 2.01 (m, 1H), 1.73 (qd, J = 6.4, 13.1 Hz, 1H) 102

  (±)-4-(3-{4,5-dichloro-6- [2- (dimethylamino)ethoxy]-1-methyl-1H-indole-2- amido}oxolan-3-yl)benzoic acid 2-chloro- N,N-dimethyl ethanamine 520.1 12.91 (br s, 1H), 9.88 (br s, 1H), 9.19 (s,1H), 7.91 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H),7.38 (s, 1H), 4.52 (t, J = 4.4 Hz, 2H), 4.21 (d, J = 5.2 Hz, 2H), 3.97(t, J = 4.4 Hz, 2 H), 3.89 (s, 3H), 3.63 (d, J = 4.4 Hz, 2H), 2.94 (s,6H), 2.75-2.70 (m, 1H), 2.33-2.30 (m, 1H) 103

  (±)-4-{3-[4,5-dichloro-1- methyl-6-(oxetan-3- ylmethoxy)-1H-indole-2-amido]oxolan-3-yl}benzoic acid AS 519.2 9.18 (s, 1H), 7.92 (d, J = 8.2Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.35 (d, J = 2.3 Hz,1H), 4.75 (dd, J = 6.0, 7.9 Hz, 2H), 4.49 (t, J = 6.4 Hz, 2H), 4.39 (d,J = 6.4 Hz, 2H), 4.25-4.18 (m, 2H), 4.00-3.93 (m, 2H), 3.89 (s, 3H),3.51- 3.43 (m, 1H), 2.78 (td, J = 6.2, 12.7 Hz, 1H), 2.32 (td, J = 8.0,13.0 Hz, 1H)

Example104—(±)-4-(3-(6-(3-Amino-2-hydroxypropoxy)-4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

To a solution of (±)-ethyl4-[3-[[4,5-dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoate(80.0 mg, 138 umol, synthesized via Method 7 Steps 1-2 as seen above inExample 95) in tetrahydrofuran (2 mL) and water (2 mL) was added lithiumhydroxide (6.65 mg, 277 umol). The mixture was stirred at 30° C. for 16hrs. On completion, the mixture was acidified by hydrochloric acid (2 N)until pH=4-5 then concentrated in vacuo. The residue was purified byPrep-HPLC (condition: water (0.225% FA)-ACN; column: Phenomenex SynergiC18 150*25*10 um) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=522.1, tR=0.630. ¹H NMR (400 MHz, DMSO-d6) δ=9.12 (s, 1H), 8.34(br. s., 1H), 7.87 (d, J=8.03 Hz, 2H), 7.46 (d, J=7.91 Hz, 2H), 7.38 (s,1H), 7.30 (s, 1H), 4.21-4.25 (m, 1H), 4.14-4.19 (m, 2H), 4.12 (d, J=6.90Hz, 2H), 3.91-3.99 (m, 3H), 3.87 (s, 3H), 3.04-3.07 (m, 1H), 2.88 (br.s., 1H), 2.75-2.79 (m, 1H), 2.27-2.32 (m, 1H).

Example105—(±)-4-(3-(6-((1H-imidazol-2-yl)methoxy)-4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

Step 1—(±)-Ethyl4-(3-(4,5-dichloro-1-methyl-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate

To a mixture of (±)-ethyl4-[3-[(4,5-dichloro-6-hydroxy-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate(300 mg, 628 umol, synthesized via Step 1 of Method 7) and2-[[2-(chloromethyl)imidazol-1-yl]methoxy] ethyl-trimethyl-silane (233mg, 943 umol) in N,N-dimethylformamide (5 mL) was added potassiumcarbonate (174 mg, 1.26 mmol) and sodium iodide (9.42 mg, 62.9 umol) inone portion at rt under nitrogen. The mixture was stirred at 80° C. for16 hrs. On completion, the mixture was cooled to rt, then mixture wasdiluted with brine (10 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (50 mL), dried oversodium sulfate, and concentrated in vacuo. The residue was purified bychromatography (petroleum ether:ethyl acetate=10:1 to 0:1) to give thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ=8.09 (d, J=8.4 Hz, 2H), 7.60(d, J=8.4 Hz, 2H), 7.18 (s, 1H), 7.18 (s, 1H), 7.11 (d, J=1.8 Hz, 2H),7.02 (s, 1H), 6.92 (s, 1H), 5.53 (s, 2H), 5.44 (s, 2H), 4.42 (q, J=7.2Hz, 2H), 4.19-4.30 (m, 4H), 3.96 (s, 3H), 3.56 (t, J=8.1 Hz, 2H),2.81-2.89 (m, 1H), 2.59-2.69 (m, 1H), 1.43 (t, J=6.9 Hz, 3H), 0.94 (t,J=8.4 Hz, 2H), 0.00 (s, 9H).

Step2—(±)-4-(3-(4,5-Dichloro-1-methyl-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methoxy)-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

To a mixture of (±)-ethyl4-[3-[[4,5-dichloro-1-methyl-6-[[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoate(75.0 mg, 109 umol) in tetrahydrofuran (2 mL) and water (2 mL) was addedlithium hydroxide (18.3 mg, 436 umol) in one portion at rt. The mixturewas stirred at 80° C. for 4 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=659.0, tR=0.817.

Step3—(±)-4-(3-(6-((1H-imidazol-2-yl)methoxy)-4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

To a mixture of(±)-4-[3-[[4,5-dichloro-1-methyl-6-[[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoic acid (45.0mg, 68.2 umol) in tetrahydrofuran (2 mL) was added hydrogenchloride/dioxane (4 M, 5 mL) in one portion at rt. The mixture wasstirred at 60° C. for 4 hrs. On completion, the mixture was concentratedin vacuo. The residue was purified by Prep-HPLC (condition: water (0.05%HCl)-ACN; column: Phenomenex Synergi C18 150*30 mm*4 um) to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=529.1, tR=0.799. ¹H NMR (400 MHz,DMSO-d6) δ=9.22 (br. s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.67 (s, 2H),7.55-7.57 (m, 3H), 7.44 (s, 1H), 5.51 (s, 2H), 4.21-4.23 (m, 2H),3.95-3.99 (m, 2H), 3.92 (s, 3H), 2.75-2.82 (m, 2H).

Example106—(±)-4-[3-[[4,5-Dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoic acid

Step 1—(±)-Methyl4,5-dichloro-1-methyl-6-[(2-oxooxazolidin-5-yl)methoxy]indole-2-carboxylate

To a solution of methyl4,5-dichloro-6-hydroxy-1-methyl-1H-indole-2-carboxylate (1.00 g, 3.65mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate(1.01 g, 7.30 mmol) and (±)-5-(chloromethyl)oxazolidin-2-one (593.71 mg,4.38 mmol, CAS #22625-57-6). The mixture was stirred at 100° C. for 12hrs. On completion, the reaction mixture was quenched with water (50 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (2×25 mL), dried over sodium sulfate, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1 to 0:1) to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.67 (s, 1H), 7.41 (s, 1H),7.16 (s, 1H), 5.06-4.97 (m, 1H), 4.43-4.28 (m, 2H), 4.03 (s, 3H), 3.86(s, 3H), 3.68 (t, J=9.03 Hz, 1H), 3.42 (dd, J=8.53, 6.78 Hz, 1H).

Step2—(±)-Methyl4,5-dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carboxylate

To a solution of (±)-methyl4,5-dichloro-1-methyl-6-((2-oxooxazolidin-5-yl)methoxy)-1H-indole-2-carboxylate(700 mg, 1.88 mmol) in N,N-dimethylformamide (24 mL) was added sodiumhydride (113 mg, 2.81 mmol, 60% purity) at 0° C. The mixture was stirredat 0° C. for 30 min, then iodomethane (532 mg, 3.75 mmol) was added. Themixture was stirred at rt for 2 hrs. On completion, the mixture wasquenched with water (200 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (2×50 mL), dried oversodium sulfate, filtered and concentrated in vacuo. The residue wastriturated with petroleum ether:ethyl acetate=1:1 and the solid wascollected by filtration to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=7.40 (s, 1H), 7.17 (s, 1H), 4.98-4.91 (m, 1H), 4.33-4.48 (m,1H), 4.34-4.28 (m, 1H), 4.03 (s, 3H), 3.86 (s, 3H), 3.76 (t, J=9.03 Hz,1H), 3.47 (dd, J=8.78, 6.02 Hz, 1H), 2.81 (s, 3H).

Step3—(±)-4,5-Dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carboxylicacid

To a solution of (±)-methyl4,5-dichloro-1-methyl-6-((3-methyl-2-oxooxazolidin-5-yl)methoxy)-1H-indole-2-carboxylate(90.0 mg, 232.4 umol) in tetrahydrofuran (5 mL) and water (2 mL) wasadded lithium hydroxide (19.5 mg, 464.9 umol). The mixture was stirredat rt for 2 hrs. On completion, the reaction mixture was concentrated toremove the organic solvent. The aqueous phase was acidified withhydrochloric acid (1 N) until pH=2, and extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with brine (2×5 mL),dried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ=7.40 (s, 1H), 7.13 (s,1H), 4.94 (td, J=8.72, 5.65 Hz, 1H), 4.43-4.27 (m, 2H), 4.05-4.01 (m,3H), 3.76 (t, J=9.03 Hz, 1H), 3.47 (dd, J=8.78, 6.27 Hz, 1H), 2.81 (s,3H).

Step4—(±)-Ethyl4-[3-[[4,5-dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoate

To a solution of(±)-4,5-dichloro-1-methyl-6-((3-methyl-2-oxooxazolidin-5-yl)methoxy)-1H-indole-2-carboxylic acid (75.0 mg, 201 umol) indichloromethane (5 mL) was added triethylamine (40.7 mg, 402 umol),ethyl 4-(3-aminotetrahydrofuran-3-yl)benzoate (52.0 mg, 221 umol) andHATU (76.41 mg, 200.97 umol). The mixture was stirred at rt for 2 hr. Oncompletion, the reaction mixture was quenched with water (20 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (2×15 mL), dried over sodium sulfate, and concentratedin vacuo. The residue was purified by chromatography (petroleumether:ethyl acetate=5:1 to 0:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ=9.21 (s, 1H), 7.94 (d, J=8.53 Hz, 2H), 7.58 (d, J=8.53Hz, 2H), 7.43-7.33 (m, 2H), 4.97-4.89 (m, 1H), 4.42-4.36 (m, 1H),4.34-4.27 (m, 3H), 4.25-4.18 (m, 2H), 4.01-3.93 (m, 2H), 3.88 (s, 3H),3.76 (t, J=8.91 Hz, 1H), 3.47-3.43 (m, 1H), 2.81 (s, 3H), 2.72-2.69 (m,1H), 2.36-2.28 (m, 1H), 1.31 (t, J=7.03 Hz, 3H).

Step5—(±)-4-[3-[[4,5-Dichloro-1-methyl-6-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]indole-2-carbonyl]amino]tetrahydrofuran-3-yl]benzoic acid

To a solution of(±)-ethyl4-(3-(4,5-dichloro-1-methyl-6-((3-methyl-2-oxooxazolidin-5-yl)methoxy)-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate(40.0 mg, 67.7 umol) in tetrahydrofuran (1 mL) and water (500 uL) wasadded lithium hydroxide (5.42 mg, 135 umol). The mixture was stirred atrt for 12 hrs. On completion, the reaction was concentrated in vacuo toremove the organic solvent. The aqueous phase was acidified withhydrochloric acid (1 N) until pH=2, and concentrated in vacuo. Theresidue was purified by Prep-HPLC (Phenomenex Synergi C18 150*30 mm*4um, water (0.225% FA)-ACN) to give the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=9.14 (s, 1H), 8.39 (s, 1H), 7.90 (d, J=8.03 Hz, 2H), 7.48 (d,J=8.28 Hz, 2H), 7.40 (s, 1H), 7.35 (s, 1H), 4.93 (d, J=5.02 Hz, 1H),4.35-4.42 (m, 1H), 4.29 (dd, J=11.04, 5.02 Hz, 1H), 4.22-4.27 (m, 1H),4.15-4.20 (m, 1H), 3.93-3.99 (m, 2H), 3.89 (s, 3H), 3.76 (t, J=8.91 Hz,1H), 3.47 (d, J=2.51 Hz, 1H), 2.81 (s, 3H), 2.74-2.79 (m, 1H), 2.26-2.33(m, 1H).

Example 107 (Method8)—2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)Phenyl)-2-methylpropanoicacid

Step 1—Allyl2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)-2-methylpropanoate

To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (150 mg,614 umol) and DMF (4.49 mg, 61.4 umol) in dichloromethane (10 mL) wasadded oxalyl chloride (390 mg, 3.07 mmol) in one portion at rt undernitrogen. The mixture was stirred at rt for 1 hr. On completion, themixture was concentrated in vacuo. To a mixture of allyl2-[4-(3-aminooxetan-3-yl)phenyl]-2-methyl-propanoate (150 mg, 544 umol)and diisopropylethylamine (211 mg, 1.63 mmol) in dichloromethane (10 mL)was added 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (171 mg, 653umol) in dichloromethane (10 mL) in one portion at rt under nitrogen.The mixture was stirred at rt for 16 hours. On completion, the reactionwas quenched with 1 mL of ethanol. Then the mixture was diluted withwater (10 mL) and extracted with dichloromethane (3×30 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was purified by column chromatography (petroleumether:ethyl acetate=20:1 to 8:1) to afford the title compound. LCMS:(ES⁺) m/z (M+H)⁺=501.2, tR=1.038.

Step2—2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)Phenyl)-2-methylpropanoicacid

To a mixture of allyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-methyl-propanoate(80.0 mg, 159 umol) and Pd(PPh₃)₄ (36.8 mg, 31.9 umol) in anhydroustetrahydrofuran (5 mL) was added morpholine (139 mg, 1.60 mmol, 140 uL)in one portion at rt under nitrogen. The mixture was stirred at 50° C.for 16 hours. On completion, the reaction mixture was concentrated invacuo, the residue was dissolved in dichloromethane (10 mL) and washedwith 1N citric acid (5 mL) until pH=3-4. The organic layer was driedover anhydrous sodium sulfate, filtrated and concentrated in vacuo. Thecrude product was dissolved in anhydrous tetrahydrofuran (10 mL) andthiourea (resin) (1.00 g, 13.1 mmol) was added. The mixture was stirredat rt for 16 hours. The reaction mixture was filtered and the filtratewas concentrated in vacuo to give a residue. The residue was purified bypre-HPLC (Instrument: GX-D; Condition: water (0.225% FA)-ACN; Column:Boston Green ODS150*30 5 u) to afford the title compound. LCMS: (ES⁺)m/z (M+H)⁺=461.2, tR=0.930. ¹H NMR (400 MHz, DMSO-d₆) δ=9.74 (s, 1H),7.63 (d, J=9.0 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.8 Hz, 1H),7.44-7.35 (m, 3H), 5.05 (d, J=6.8 Hz, 2H), 4.79 (d, J=6.8 Hz, 2H), 3.97(s, 3H), 1.47 (s, 6H).

Method 8 Table: Compounds Synthesized via Method 8 using the appropriateacid and amine LCMS Ex- Inter- Inter- (ES+) ample mediate mediate m/zHNMR (400 MHz, # Structure Acid Amine (M + H)⁺ DMSO-d6) δ 108

  1-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]phenyl}cyclopropane-1- carboxylic acid A BU 459.2 9.73 (s, 1H), 7.63(d, J = 8.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.42 (s, 1H), 7.35 (d, J = 8.0Hz, 2H), 5.06 (d, J = 7.2 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 3.98 (s,3H), 1.40 (d, J = 2.4 Hz, 2H), 1.07 (d, J = 2.4 Hz, 2H) 109

  2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]-3-fluorophenyl}-2- methylpropanoic acid A BV 479.2 9.85 (s, 1H), 7.60 (d,J = 8.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.39 (s, 1H), 7.21-7.18 (m, 2H),5.05- 495 (m, 4H), 3.94 (s, 3H), 1.42 (s, 6H) 110

  2-{4-[3-(4-chloro-5-methoxy- 1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}- 2-methylpropanoic acid B BT 457.3 9.64 (s,1H), 7.58-7.49 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.25 (d,J = 9.0 Hz, 1H), 5.05 (d, J = 6.5 Hz, 2H), 4.78 (d, J = 6.5 Hz, 2H),3.94 (s, 3H), 3.89 (s, 3H), 1.47 (s, 6H) 111

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}- 2-cyclobutylacetic acid B CA 483.3 9.63 (s,1H), 7.57-7.48 (m, 3H), 7.36-7.28 (m, 3H), 7.25 (d, J = 8.9 Hz, 1H),5.04 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.89(s, 3H), 3.49 (d, J = 10.8 Hz, 1H), 2.88 (m, 1H), 2.11 (m, 1H), 1.76 (m,4H), 1.55 (m, 1H) 112

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole- 2-amido)oxetan-3-yl]phenyl}pentanoic acid B CE 471.3 9.62 (s, 1H), 7.57-7.46 (m, 3H),7.37-7.28 (m, 3H), 7.24 (d, J = 9.0 Hz, 1H), 5.03 (d, J = 6.5 Hz, 2H),4.77 (d, J = 6.5 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.44 (t, J = 7.8Hz, 1H), 1.97-1.86 (m, 1H), 1.61-1.51 (m, 1H), 1.29- 1.13 (m, 2H), 0.85(t, J = 7.2 Hz, 3H) 113

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}butanoic acid F BZ 491.2 9.60 (s, 1H), 7.52(d, J = 8.0 Hz, 2H), 7.39-7.31 (m, 3H), 7.28 (s, 1H), 5.04 (d, J = 6.8Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.39-3.39(m, 1H), 2.05- 1.90 (m, 1H), 1.66-1.63 (m, 1H), 0.84 (t, J = 7.3 Hz, 3H)114

  (±)-2-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]phenyl}pentanoic acid A CE 475.2 9.74 (s, 1H), 7.62 (d, J = 8.9 Hz,1H), 7.53 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.42 (s, 1H),7.33 (d, J = 8.3 Hz, 2H), 5.05 (d, J = 6.8 Hz, 2H), 4.79 (d, J = 6.7 Hz,2H), 3.97 (s, 3H), 3.51-3.45 (t, J = 7.3 Hz, 1H), 1.99- 1.87 (m, 1H),1.67-1.55 (m, 1H), 1.33-1.13 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H) 115

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}pentanoic acid F CE 505.0 9.59 (s, 1H), 7.51(d, J = 8.3 Hz, 2H), 7.37-7.31 (m, 3H), 7.29 (s, 1H), 5.03 (d, J = 6.8Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 2.68 (s,1H), 1.93 (d, J = 9.2 Hz, 1H), 1.60 (d, J = 8.7 Hz, 1H), 1.28-1.15 (m,2H), 0.87 (t, J = 7.3 Hz, 3H) 116

  (±)-2-cyclobutyl-2-{4-[3- (4,5-dichloro-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}acetic acid A CA 487.3 9.72 (s, 1H),7.63 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.8 Hz,1H), 7.42 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 5.05 (d, J = 6.8 Hz, 2H),4.78 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.53 (d, J = 11.0 Hz, 1H), 2.87(td, J = 7.5, 10.8 Hz, 1H), 2.16- 2.04 (m, 1H), 1.85- 1.67 (m, 4H),1.62-1.49 (m, 1H) 117

  (±)-2-cyclobutyl-2-{4-[3-(4,5- dichloro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}acetic acid F CA 517.2 9.58 (s,1H), 7.51 (d, J = 8.3 Hz, 2H), 7.36 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H),7.29 (s, 1H), 5.03 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 3.97(s, 3H), 3.96 (s, 3H), 3.50 (d, J = 10.9 Hz, 1H), 2.92-2.82 (m, 1H),2.13-2.07 (m, 1H), 1.84-1.68 (m, 4H), 1.59-1.49 (m, 1H) 118

  (±)-2-cyclopentyl-2-{4-[3-(4,5- dichloro-6-methoxy-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}acetic acid F CC 531.3 9.59 (s,1H), 7.52 (d, J = 8.2 Hz, 2H), 7.37 (m, 3H), 7.29 (s, 1H), 5.04 (d, J =6.8 Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.22(d, J = 10.8 Hz, 1H), 2.43 (m., 1H), 1.93-1.79 (m, 1H), 1.67-1.50 (m,3H), 1.43 (m, 1H), 1.35-1.22 (m, 2H), 0.97-0.93 (m, 1H) 119

  (±)-ethoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}-2-cyclohexylacetic acid B CJ 511.3 9.63 (s, 1H), 7.55-7.46(m, 3H), 7.37-7.30 (m, 3H), 7.25 (d, J = 9.3 Hz, 1H), 5.04 (d, J = 6.8Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.12 (d,J = 10.3 Hz, 1H), 1.93-1.80 (m, 2H), 1.69 (d, J = 10.8 Hz, 1H),1.59-1.50 (m, 2H), 1.21 (d, J = 10.3 Hz, 2H), 1.17- 0.94 (m, 3H), 0.72(d, J = 11.0 Hz, 1H) 120

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H- indole-2-amido)oxetan-3-yl]phenyl}-2-(oxan-4- yl)acetic acid B CK 513.3 9.63 (s, 1H), 7.56-7.49(m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J = 9.0 Hz,1H), 5.04 (d, J = 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 3.91 (d, J =17.8 Hz, 6H), 3.86 (d, J = 14.3 Hz, 1H), 3.73 (d, J = 11.0 Hz, 1H), 3.29(t, J = 11.3 Hz, 1H), 3.19 (d, J = 10.0 Hz, 2H), 2.10 (d, J = 16.8 Hz,1H), 1.72 (d, J = 12.3 Hz, 1H), 1.37-1.19 (m, 1H), 1.09- 0.98 (m, 2H)121

  (±)-2-{4-[3-(4-chloro-5- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}- 2-(piperidin-4-yl)acetic acid B CM 512.29.63 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.34(d, J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J = 9.2 Hz, 1H), 5.04 (d, J= 6.8 Hz, 2H), 4.77 (d, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H),3.15-3.06 (m, 1H), 2.94 (d, J = 11.3 Hz, 1H), 2.27-2.21 (m, 3H), 2.08-1.78 (m, 2H), 1.27- 1.14 (m, 2H), 0.97 (d, J = 9.9 Hz, 1H) 122

  (±)-2-{4-[3-(4,5-dichloro-6- methoxy-1-methyl-1H-indole-2-amido)oxetan-3-yl]phenyl}- 4-methylpentanoic acid F CN 519.2 9.60 (s,1H), 7.52 (d, J = 8.3 Hz, 2H), 7.39-7.31 (m, 3H), 7.28 (s, 1H), 5.04 (d,J = 6.5 Hz, 2H), 4.78 (d, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.96 (s, 3H),3.58-3.49 (m, 1H), 1.92- 1.77 (m, 1H), 1.54 (td, J = 6.9, 13.5 Hz, 1H),1.40 (td, J = 6.6, 13.2 Hz, 1H), 0.86 (d, J = 6.3 Hz, 6H) 123

  (±)-3-cyclopropyl-2-{4-[3- (4,5-dichloro-6-methoxy-1-methyl-1H-indole-2- amido)oxetan-3- yl]phenyl}propanoic acid F CO 517.29.53 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.30-7.23 (m, 3H), 7.20 (s, 1H),4.96 (d, J = 6.8 Hz, 2H), 4.70 (d, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.87(s, 3H), 3.47 (t, J = 7.4 Hz, 1H), 1.83-1.73 (m, 1H), 1.45 (m, 1H),0.60-0.46 (m, 1H), 0.33-0.19 (m, 2H), 0.08-−0.10 (m, 2H) 124

  (±)-3-cyclopropyl-2-{4-[3- (4,5-dichloro-1-methyl-1H-indole-2-amido)oxetan-3- yl]phenyl}propanoic acid A CO 487.2 9.74 (s,1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.47 (d, J =8.8 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 5.05 (d, J = 6.8Hz, 2H), 4.78 (d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.58 (t, J = 7.4 Hz,1H), 1.94-1.77 (m, 1H), 1.55 (td, J = 6.6, 13.6 Hz, 1H), 0.73-0.51 (m,1H), 0.35 (d, J = 7.8 Hz, 2H), 0.16-0.06 (m, 2H)  125^(a)

  (±)-3-{4-[3-(4,5-dichloro-1- methyl-1H-indole-2- amido)oxetan-3-yl]phenyl}oxolane-3- carboxylic acid A CR 489.1 9.75 (s, 1H), 7.63 (d, J= 9.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 3H), 7.41 (s, 1H), 7.33 (d, J = 7.9Hz, 2H), 5.03 (d, J = 6.8 Hz, 2H), 4.76 (d, J = 6.8 Hz, 2H), 4.59 (d,.76.1 Hz, 1H), 3.95 (s, 3H), 3.81-3.72 (m, 1H), 3.63 (d, J = 8.5 Hz,1H), 2.99-2.90 (m, 1H), 2.53-2.53 (m, 1H) ^(a)Step 1 was run at 0° C.for 1 hr. Step 2 was run at rt for 12 hrs.

Example126—(±)-2-(4-(3-(4-chloro-5-methoxy-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)butanoic acid

To a solution of (±)-allyl2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]butanoate (724 mg, 945 umol, synthesized via Method8, Step 1 with acid B and amine BZ) and morpholine (823 mg, 9.45 mmol)in tetrahydrofuran (10 mL) was added Pd(PPh₃)₄ (218 mg, 189 umol) undera nitrogen. The reaction mixture was stirred at 40° C. for 12 hrs. Oncompletion, the reaction mixture was concentrated in vacuo, the residuewas dissolved in dichloromethane (50 mL) and washed with 1N citric acid(5 mL) until pH=3-4. The organic layer was dried over anhydrous sodiumsulfate, filtrated and concentrated in vacuo. The crude product wasdissolved in anhydrous tetrahydrofuran (30 mL) and thiourea (resin)(1.00 g, 13.1 mmol) was added. The mixture was stirred at rt for 16hours. Then the reaction mixture was filtrated and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini 150*25 mm*10 um;Condition: water (0.05% ammonia hydroxide v/v)-ACN] to give the titlecompound. LCMS: (ES⁺) m/z (M+1)⁺=457.2, tR=0.823. ¹H NMR (400 MHz,DMSO-d₆) δ=9.63 (s, 1H), 7.57-7.48 (m, 3H), 7.36-7.29 (m, 3H), 7.25 (d,J=9.0 Hz, 1H), 5.04 (d, J=6.8 Hz, 2H), 4.78 (d, J=6.6 Hz, 2H), 3.94 (s,3H), 3.89 (s, 3H), 3.44 (t, J=7.8 Hz, 1H), 2.00-1.92 (m, 1H), 1.62 (td,J=7.1, 13.7 Hz, 1H), 0.83 (t, J=7.4 Hz, 3H).

Example127—(±)-2-[4-[3-[(4-Chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]phenyl]-3-methyl-butanoicacid

To a solution of (±)-allyl2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoate(300 mg, 587 umol, synthesized via Step 1 of Method 8 with acid B andamine CB) and morpholine (51 mg, 587 umol) in tetrahydrofuran (10 mL)was added Pd(PPh₃)₄ (67.8 mg, 58.7 umol) under a nitrogen atmosphere,and the mixture was stirred at 50° C. for 12 hrs. On completion, themixture was concentrated in vacuo to give a residue. The residue waswashed with 1N HCl (3 mL), diluted with water (20 mL) and extracted withethyl acetate (2×30 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give aresidue. The residue was dissolved in tetrahydrofuran (20 mL) andthiourea (resin) (44.7 mg, 587.07 umol) was added. The mixture wasstirred at rt for 2 hours. Then the reaction mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified with prep-HPLC (Instrument: GX-D; Column: PhenomenexSynergi C18 150*25*10 um; Mobile phase: 0.225% formic acid-acetonitrile)to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=471.3, tR=0.891. ¹HNMR (400 MHz, DMSO-d₆) δ=9.63 (s, 1H), 7.57-7.48 (m, 3H), 7.39-7.32 (m,2H), 7.31 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 5.05 (d, J=6.8 Hz, 2H), 4.78(d, J=6.8 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.06 (d, J=10.4 Hz, 1H),2.28-2.12 (m, 1H), 1.00 (d, J=6.4 Hz, 3H), 0.64 (d, J=6.7 Hz, 3H).

Example 128 &129—(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid &(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid

(±)-2-[4-[3-[(4-Chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid (300 mg, 637 umol, Example 127) was purified by chiral SFC(Instrument: SFC-1; Column: OD (250 mm*30 mm, 10 um); Condition:Base-methanol) to give Example 128(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid or(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid (77.0 mg, ee: 100%, cSFC, tR=0.993) andimpure Example 129(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid or(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid (120 mg, ee: 93%, cSFC, tR=1.147). Then impure Example 128 wasfurther purified by chiral SFC (Instrument: SFC-1; Column: AD (250 mm*30mm, 10 um); Condition: Base-methanol) to give Example 128(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid or(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid (95.5 mg, ee: 100%). Example 128(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid or(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoic acid (77.0 mg, ee: 100%) was obtained as ayellow solid. LCMS: (ES⁻) m/z (M−H)⁻=471.2, tR=0.871. cSFC, tR=0.993. ¹HNMR (400 MHz, DMSO-d₆) δ=9.63 (s, 1H), 7.53 (dd, J=2.6, 8.7 Hz, 3H),7.35 (d, J=8.3 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 5.04 (d,J=6.8 Hz, 2H), 4.78 (d, J=7.3 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.08(d, J=10.3 Hz, 1H), 2.21 (td, J=6.5, 10.4 Hz, 1H), 1.00 (d, J=6.4 Hz,3H), 0.64 (d, J=6.7 Hz, 3H).

Example 129(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid or(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid (95.5 mg, ee: 100%) was obtained as a yellow solid. LCMS: (ES⁻) m/z(M−H)⁻=471.2, tR=0.871. cSFC, tR=1.147. ¹H NMR (400 MHz, DMSO-d₆) δ=9.62(s, 1H), 7.49-7.55 (m, 3H), 7.34 (d, J=8.3 Hz, 2H), 7.30 (s, 1H), 7.25(d, J=9.2 Hz, 1H), 5.04 (d, J=6.8 Hz, 2H), 4.78 (d, J=6.4 Hz, 2H), 3.94(s, 3H), 3.89 (s, 3H), 3.07 (d, J=10.7 Hz, 1H), 2.21 (dd, J=17.1, 6.6Hz, 1H), 1.00 (d, J=6.4 Hz, 3H).

Example130—(±)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]-oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid

To a solution of (±)-allyl2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-acetate(1.70 g, 3.17 mmol, synthesized via Step 1 of Method 8 with acid B andamine CC) and morpholine (1.66 g, 19.0 mmol) in tetrahydrofuran (30 mL)was added Pd(PPh₃)₄ (366 mg, 317 umol) under a nitrogen atmosphere, andthe mixture was stirred at 50° C. for 24 hrs. On completion, the mixturewas concentrated in vacuo to give a residue. The residue was washed withcitric acid (50 mL), and extracted with ethyl acetate (2×60 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated in vacuum to give a residue. The residue was dissolvedin tetrahydrofuran (50 mL) and thiourea (resin) (5 g) was added. Themixture was stirred at 25° C. for 3 hours. Then the reaction mixture wasfiltrated and the filtrate was concentrated in vacuo to give a residue.The residue was purified with prep-HPLC (Instrument: HPLC-A; Column:Phenomenex Gemini C18 250*50 mm*10 um; Mobile phase: 0.225% formicacid-acetonitrile) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=497.3, tR=0.925. ¹H NMR (400 MHz, DMSO-d₆) δ=12.28 (br. s., 1H),9.63 (s, 1H), 7.54 (d, J=8.4 Hz, 3H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (s,1H), 7.25 (d, J=9.0 Hz, 1H), 5.05 (d, J=6.7 Hz, 2H), 4.78 (d, J=6.8 Hz,2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.25 (d, J=11.0 Hz, 1H), 2.48-2.40 (m,1H), 1.92-1.77 (m, 1H), 1.70-1.49 (m, 3H), 1.49-1.37 (m, 1H), 1.36-1.16(m, 2H), 0.97 (qd, J=8.2, 12.4 Hz, 1H).

Example 131 &132—(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid &(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid

(±)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid (570 mg, 1.15 mmol, Example 130) was purified with SFC(“AS-3S_5_5_40_3ML Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um Mobilephase: ethanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/minWavelength: 220 nm”) to give(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid or(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid (254 mg, 44% yield) (peak 1: cSFC=3.201) and(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid or(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid (276 mg, 48% yield) (peak 2: cSFC=3.570).(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid or(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid (Example 131) (peak 1: cSFC=3.201): LCMS: (ES⁺) m/z (M+H)⁺=497.3,tR=0.934. ¹H NMR (400 MHz, DMSO-d₆) δ=9.64 (s, 1H), 7.56-7.51 (m, 3H),7.37 (d, J=8.0 Hz, 2H), 7.31 (s, 1H), 7.26 (d, J=9.3 Hz, 1H), 5.04 (d,J=6.9 Hz, 2H), 4.78 (d, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.23(d, J=10.8 Hz, 1H), 2.44-2.41 (m, 1H), 1.87-1.80 (m, 1H), 1.63-1.50 (m,3H), 1.45-1.40 (m, 1H), 1.32-1.22 (m, 2H), 1.00-0.92 (m, 1H).

(2R)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid or(2S)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-cyclopentyl-aceticacid (Example 132) (peak 2: cSFC=3.570): LCMS: (ES⁺) m/z (M+H)⁺=497.3,tR=0.930. ¹H NMR (400 MHz, DMSO-d₆) δ=12.55-11.72 (m, 1H), 9.63 (s, 1H),7.56-7.51 (m, 3H), 7.37 (d, J=8.3 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J 9.2Hz, 1H), 5.05 (d, J=6.8 Hz, 2H), 4.78 (d, J=7.5 Hz, 2H), 3.94 (s, 3H),3.89 (s, 3H), 3.24 (d, J=11.0 Hz, 1H), 2.48-2.41 (m, 1H), 1.89-1.78 (m,1H), 1.66-1.49 (m, 3H), 1.47-1.37 (m, 1H), 1.37-1.11 (m, 3H), 0.97 (m,1H).

Example133—(±)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)butanoicacid

To a solution of(±)-allyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]butanoate (746 mg, 1.07 mmol, synthesized via Step 1 of Method 8with acid A and amine BZ) and morpholine (931 mg, 10.7 mmol) intetrahydrofuran (10 mL) was added Pd(PPh₃)₄ (247 mg, 214 umol) under anitrogen. The reaction mixture was stirred at 40° C. for 12 hrs. Oncompletion, the reaction mixture was concentrated in vacuo, and theresidue was dissolved in dichloromethane (50 mL) and washed with 1Ncitric acid (5 mL) until pH=3-4. The organic layer was dried overanhydrous sodium sulfate, filtrated and concentrated in vacuo. The crudeproduct was dissolved in anhydrous tetrahydrofuran (30 mL) and thiourea(resin) (1.00 g, 13.1 mmol) was added. The mixture was stirred at rt for16 hours. Then the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC [Instrument: GX-F; Column: Boston Green ODS 150*30 5 u;Condition: water (0.225% FA)-ACN] to give the title compound. LCMS:(ES⁺) m/z (M+1)⁺=461.3, tR=0.883. ¹H NMR (400 MHz, DMSO-d₆) δ=9.73 (s,1H), 7.63 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.48 (d, J=9.0 Hz,1H), 7.42 (s, 1H), 7.33 (d, J=8.3 Hz, 2H), 5.05 (d, J=6.8 Hz, 2H), 4.79(d, J=6.8 Hz, 2H), 3.97 (s, 3H), 3.44 (t, J=7.8 Hz, 1H)), 2.02-1.93 (m,1H), 1.65 (td, J=7.1, 13.7 Hz, 1H), 0.84 (t, J=7.3 Hz, 3H).

Example134—(±)-2-[4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid

To a solution of (±)-allyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoate(500 mg, 970 umol, synthesized via Step 1 of Method 8 with acid A andamine CB) and morpholine (507 mg, 5.82 mmol) in tetrahydrofuran (20 mL)was added Pd(PPh₃)₄ (112 mg, 97.0 umol) under nitrogen, and the mixturewas stirred at 40° C. for 16 hours. On completion, the mixture wasconcentrated, washed with 100 mL water, and extracted with ethyl acetate(3×50 mL). The organic layer was dried with anhydrous sodium sulfate,filtrated and concentrated. The residue was dissolved in 20 mL oftetrahydrofuran and thiourea (resin) (1.00 g, 13.1 mmol) was added. Themixture was stirred at rt for 2 hours. Then the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (condition: water (0.225% FA)-ACN;column: Boston Green ODS 150*30 5 u) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=475.1, tR=0.890. ¹H NMR (400 MHz, DMSO-d6) δ=9.72 (s,1H), 7.63 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.8 Hz,1H), 7.42 (s, 1H), 7.35 (d, J=8.0 Hz, 2H), 5.05 (d, J=6.5 Hz, 2H), 4.79(d, J=6.5 Hz, 2H), 3.97 (s, 3H), 3.11 (d, J=10.3 Hz, 1H), 2.22 (td,J=6.6, 10.5 Hz, 1H), 1.01 (d, J=6.3 Hz, 3H), 0.65 (d, J=6.8 Hz, 3H).

Example135—(±)-2-[4-[3-[(4,5-Dichloro-6-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoicacid

To a solution of (±)-allyl2-[4-[3-[(4,5-dichloro-6-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-3-methyl-butanoate(500 mg, 917 umol, synthesized via Step 1 of Method 8 with acid F andamine CB) and morpholine (479 mg, 5.50 mmol) in tetrahydrofuran (10 mL)was added Pd(PPh₃)₄ (106 mg, 91.7 umol) under nitrogen, and the mixturewas stirred at 40° C. for 16 hours. On completion, the mixture wasconcentrated and washed with 100 mL water and extracted with ethylacetate (3×50 mL). The organic layer was dried with anhydrous sodiumsulfate, filtrated and concentrated. The residue was dissolved in 20 mLtetrahydrofuran and thiourea (resin) (1.00 g, 13.1 mmol) was added. Themixture was stirred at rt for 2 hours. Then the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (condition: water (0.225% FA)-ACN;column: Boston Green ODS 150*30 5 u) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=505.2, tR=0.938. ¹H NMR (400 MHz, DMSO-d6) δ=9.58 (s,1H), 7.53 (d, J=8.3 Hz, 2H), 7.40-7.32 (m, 3H), 7.29 (s, 1H), 5.04 (d,J=6.5 Hz, 2H), 4.78 (d, J=6.5 Hz, 2H), 3.97 (d, J=2.3 Hz, 6H), 3.10 (d,J=10.5 Hz, 1H), 2.29-2.16 (m, 1H), 1.01 (d, J=6.5 Hz, 3H), 0.65 (d,J=6.8 Hz, 3H).

Example136—(±)-2-Cyclopentyl-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]acetic acid

To a mixture of (±)-allyl2-cyclopentyl-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]acetate(100 mg, 185 umol, synthesized via Step 1 of Method 8 with acid A andamine CC) in tetrahydrofuran (5.00 mL) was added Pd(PPh₃)₄ (21.3 mg,18.5 umol) and morpholine (96.5 mg, 1.11 mmol) in one portion at rtunder N₂. The mixture was stirred at rt for 16 hrs. On completion, thereaction was concentrated in vacuo, the residue was dissolved indichloromethane (10 mL) and washed with citric acid. Then the organiclayer was separated and concentrated in vacuo. The residue was dissolvedin tetrahydrofuran (10 mL) and thiourea (resin) (1.00 g, 13.1 mmol) wasadded and the mixture was stirred at 25° C. for 16 hours. The mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by Prep-HPLC (condition: water (0.225% FA)-ACN; PhenomenexSynergi C18 150*25*10 um) to give the title compound. LCMS (ES⁺): m/z(M+H)⁺=501.2, tR=0.947 min. ¹H NMR (400 MHz, DMSO-d₆) δ=9.70 (s, 1H),7.63 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.8 Hz, 1H),7.40 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 5.05 (d, J=6.8 Hz, 2H), 4.78 (d,J=6.4 Hz, 2H), 3.96 (s, 3H), 3.34-3.19 (m, 1H), 2.50-2.44 (m, 1H),1.84-1.82 (m, 1H), 1.59-1.53 (m, 3H), 1.51-1.50 (m, 1H), 1.29-1.23 (m,2H), 0.95-0.90 (m, 1H).

Example137—(±)-2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)-4-methylpentanoicacid

To a mixture of (±)-allyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-4-methyl-pentanoate (75.0 mg, 141 umol, synthesized via Step 1of Method 8 with acid A and amine CN) and Pd(PPh₃)₄ (32.7 mg, 28.3 umol)in anhydrous tetrahydrofuran (5 mL) was added morpholine (123 mg, 1.42mmol, 124 uL) in one portion at rt under nitrogen. The mixture wasstirred at 50° C. for 16 hours. On completion, the reaction mixture wasconcentrated in vacuo, the residue was dissolved in dichloromethane (10mL) and washed with 1N citric acid (5 mL) until pH=3-4. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The crude product was dissolved in anhydrous tetrahydrofuran(10 mL) and thiourea (resin) (1.00 g, 13.1 mmol) was added. The mixturewas stirred at rt for 16 hours. The reaction mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified by pre-HPLC (Instrument: GX-D; Condition: water (0.225%FA)-ACN; Column: Boston Green ODS150*30 5 u) to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=511.2, tR=0.986. ¹H NMR (400 MHz, DMSO-d₆) δ=9.74(s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.8Hz, 1H), 7.42 (s, 1H), 7.35 (d, J=8.0 Hz, 2H), 5.05 (d, J=6.5 Hz, 2H),4.78 (d, J=6.8 Hz, 2H), 3.97 (s, 3H), 3.54 (br. s., 1H), 1.91-1.75 (m,1H), 1.54 (td, J=6.9, 13.5 Hz, 1H), 1.47-1.30 (m, 1H), 0.86 (d, J=6.5Hz, 6H).

Example138—(±)-2-[4-[3-[(4-Chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-(4-hydroxycyclohexyl)aceticacid

Step 1—(±)-Allyl2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-(4-hydroxycyclohexyl)acetate

To a solution of (±)-allyl2-(4-acetoxycyclohexyl)-2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]acetate(130 mg, 213 umol, synthesized via Method 8 Step 1 with acid B and amineCQ) in tetrahydrofuran (10 mL) and water (2 mL) was added lithiumhydroxide (35.7 mg, 1.49 mmol) and methanol (5 mL), and the mixture wasstirred at rt for 12 hrs. On completion, the mixture was diluted withsaturated ammonium chloride (10 mL) and extracted with ethyl acetate(3×15 mL). The combined organic layer was washed with brine (3×20 mL),dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by Prep-TLC (petroleum ether:ethyl acetate=2:3) togive the title compound. LCMS: (ES⁺) m:z (M+H)⁺=567.2, tR=0.890.

Step2—(±)-2-[4-[3-[(4-Chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-(4-hydroxycyclohexyl)aceticacid

To a solution of (±)-allyl2-[4-[3-[(4-chloro-5-methoxy-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]-2-(4-hydroxycyclohexyl)acetate (80.0 mg, 141 umol)and morpholine (73.7 mg, 846 umol) in tetrahydrofuran (20 mL) was addedPd(PPh₃)₄ (16.3 mg, 14.1 umol) under a nitrogen atmosphere, and themixture was stirred at 40° C. for 16 hrs. On completion, the mixture wasconcentrated, washed with water (15 mL) and extracted with ethyl acetate(3×20 mL). The organic layer was dried with anhydrous sodium sulfate,filtrated and concentrated. The residue was dissolved in tetrahydrofuran(20 mL) and thiourea (resin) (100 mg, 1.31 mmol) was added. The mixturewas stirred at rt for 12 hrs. Then the reaction mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified by prep-HPLC (condition: water (0.05% ammonia hydroxidev/v)-ACN; column: Phenomenex Gemini 150*25 mm*10 um) to give the titlecompound. LCMS: (ES⁺) m:z (M+H)⁺=527.0, (M+39)⁺=564.9, tR=0.708. ¹H NMR(400 MHz, DMSO-d₆) δ=9.61 (s, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.47 (d,J=7.8 Hz, 2H), 7.32-7.29 (m, 3H), 7.24 (d, J=9.0 Hz, 1H), 5.03 (d, J=6.8Hz, 2H), 4.76 (d, J=6.5 Hz, 2H), 4.44 (br. s., 1H), 3.93 (s, 3H), 3.88(s, 3H), 2.99-2.93 (m, 1H), 2.42 (m, 1H), 1.82-1.79 (m 4H), 1.66-1.63(m, 1H), 1.49-1.40 (m, 1H), 1.14-1.10 (m, 2H), 1.00-0.95 (m, 1H).

Other Methods:

Example 139, 140, &141—(±)-Dichloro-N-[3-(3-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide,(±)-N-[3-(3-Carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide,&(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid

Step1—(±)-N-[3-(3-Bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (580 mg,2.38 mmol) in a mixture of dichloromethane (20 mL) andN,N-dimethylformamide (157 uL) was added oxalyl chloride (904 mg, 7.13mmol) dropwise and the reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give4,5-dichloro-1-methyl-indole-2-carbonyl chloride (597 mg, crude) as awhite solid, which was used in the next step directly.

A solution of (±)-3-(3-bromophenyl)tetrahydrofuran-3-amine (500 mg, 2.07mmol) and triethylamine (628 mg, 6.21 mmol) in dichloromethane (8 mL),was added a solution of 4,5-dichloro-1-methyl-indole-2-carbonyl chloride(597 mg, 2.28 mmol) in dichloromethane (2 mL) under nitrogen atmosphere.Then the reaction was stirred at rt for 1.5 hrs. On completion, themixture was adjusted to pH=5-6 with hydrochloric acid (1N). Then to themixture was added water (20 mL) and the solution was extracted withdichloromethane (2×15 mL). The combined organic phase was washed withbrine and concentrated to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=469.0, tR=1.024,

Step 2 (Example139)—(±)-Dichloro-N-[3-(3-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide

To a solution of(±)-N-[3-(3-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide(700 mg, 1.50 mmol) in dimethyl formamide (10 mL) was added zinc cyanide(528 mg, 4.50 mmol) and tetrakis (triphenylphosphine) palladium (173 mg,150 umol), and the mixture was stirred at 120° C. for 2 hrs. Oncompletion, to the mixture was added ethyl acetate (30 mL), then themixture was filtered, and the filtrate was washed with water (2×30 mL).The organic phase was washed with brine and filtered again and thefiltrate was concentrated to give a residue. The residue was dissolvewith petroleum ether:ethyl acetate=1:1 (10 mL) and filtered to get thefilter cake. The filter cake was dried in vacuo to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=414.0, tR=0.916. ¹H NMR (400 MHz,CDCl₃) δ=7.78 (d, J=1.4 Hz, 1H), 7.74 (dt, J=7.91, 1H), 7.56-7.62 (m,1H), 7.53-7.46 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H),7.05 (s, 1H), 6.84 (s, 1H), 4.28-4.20 (m, 1H), 4.20-4.14 (m, 3H),4.01-3.91 (m, 3H), 2.84-2.74 (m, 1H), 2.57 (dt, J=13.2, 1H).

Step 3 (Example140)—(±)-N-[3-(3-Carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-N-[3-(3-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(120 mg, 289 umol) and potassium carbonate (16 mg, 115 umol) in dimethylsulfoxide (5 mL) was added hydrogen peroxide (105 uL, 30%) in oneportion at rt, and the mixture was stirred at 20-25° C. for 2 hrs. Oncompletion, the mixture was diluted with water (20 mL) and filtered. Thefilter cake was washed with petroleum ether (2 mL), then the filter cakewas dried in vacuo to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=432.0, tR=0.868. ¹H NMR (300 MHz, dimethylsulfoxide-d6) δ=9.23(s, 1H), 8.06-7.92 (m, 2H), 7.74 (d, J=7.9 Hz, 1H), 7.64-7.54 (m, 2H),7.48-7.39 (m, 3H), 7.35 (br. s., 1H), 4.31-4.24 (m, 1H), 4.20-4.14 (m,1H), 3.96 (t, J=6.9 Hz, 2H), 3.89 (s, 3H), 2.86-2.71 (m, 1H), 2.39-2.25(m, 1H).

Step 4 (Example141)—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid

To a solution of(±)-N-[3-(3-carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-car-boxamide(100 mg, 231 umol) in methanol (10 mL) was added sodium hydroxide (10mL, 30% wt in water). Then the mixture was stirred at 90° C. for 16 hrs.On completion, the mixture was cooled to 20-25° C., then the pH wasadjusted to 1-2 with aq. hydrochloric acid (2 N), concentrated toremoved methanol, and the mixture was filtered to give the filter cake.The filter cake was purification by prep-HPLC (Phenomenex Gemini C18250×50 mm×10 um, 0.1% TFA-ACN) to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=433.0, tR=0.981, ¹H NMR (400 MHz, dimethylsulfoxide-d6)δ=9.26 (s, 1H), 8.01 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.55-7.62 (m, 2H),7.47-7.34 (m, 3H), 4.27 (d, J=9.2 Hz, 1H), 4.16 (d, J=9.2 Hz, 1H), 3.95(t, J=7.0 Hz, 2H), 3.89 (s, 3H), 2.80 (dt, J=12.5, 1H), 2.26-2.33 (m,1H).

Example 142, 143, 144, &145—(±)-N-[3-(4-Bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide,(±)-N-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)-piperidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide,(±)-N-[3-(4-Carbamoyl-phenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide,&(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid

Step 1 (Example142)—(±)-N-[3-(4-Bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (230 mg,942 umol) and N,N-dimethylformamide (4.13 mg, 56.5 umol) indichloromethane (10 mL) was added oxalyl chloride (358 mg, 2.83 mmol)dropwise at 0° C. and the reaction mixture was stirred at 25° C. for 1hr. On completion, the mixture was concentrated in vacuo to remove thesolvent to give 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (250mg, crude) which was used to the next step directly.

To a solution of (±)-3-(4-bromophenyl)tetrahydrofuran-3-amine (200 mg,826 umol) and triethylamine (208 mg, 2.07 mmol) in dichloromethane (5mL) was added a solution of 4,5-dichloro-1-methyl-indole-2-carbonylchloride (238 mg, 908 umol) in dichloromethane (5 mL) dropwise at 0° C.and the reaction was stirred at rt for 16 hrs. On completion, themixture was adjusted to pH=5-6 with hydrochloric acid solution (1N),then the mixture was added water (30 mL) and extracted with ethylacetate (2×20 mL). The combined organic phase was washed with brine andconcentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=469.0, tR=1.048, ¹H NMR (400 MHz, CDCl3) δ=7.53-7.50 (m, 2H),7.40-7.36 (m, 3H), 7.23 (d, J=8.9 Hz, 1H), 7.03 (s, 1H), 6.84 (s, 1H),4.25 (d, J=9.7 Hz, 1H), 4.16 (dd, J=5.7, 8.6 Hz, 2H), 4.11 (d, J=9.7 Hz,1H), 3.97 (s, 3H), 2.86-2.77 (m, 1H), 2.62-2.52 (m, 1H).

Step 2 (Example143)—(±)-N-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)piperidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

To a solution of(±)-N-[3-(4-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide(370 mg, 790 umol) in dimethyl formamide (5 mL) was added zinc cyanide(278 mg, 2.37 mmol) and Pd(PPh₃)₄ (91.3 mg, 79.0 umol) and the reactionmixture was stirred at 120° C. for 2 hrs. On completion, water (10 mL)was added to the reaction mixture and it was extracted with ethylacetate (2×15 mL). The combined organic phase was washed with brine andfiltered, and the filtrate was concentrated in vacuo to give a crudeproduct. The crude product was purified by column chromatography(petroleum ether:ethyl acetate=10:1-3:1) to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=414.0, tR=0.986, ¹H NMR (400 MHz, CDCl3)δ=7.72-7.66 (m, 2H), 7.64-7.59 (m, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.24 (d,J=9.0 Hz, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 4.24-4.14 (m, 4H), 3.97 (s,3H), 2.79 (td, J=6.1, 12.7 Hz, 1H), 2.59 (td, J=8.3, 13.2 Hz, 1H).

Step 3 (Example144)—(±)-N-[3-(4-Carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-N-[3-(4-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(240 mg, 579 umol) and potassium carbonate (32.0 mg, 231 umol) indimethyl sulfoxide (5 mL) was added hydrogen peroxide (249 mg, 2.20mmol) in one portion at rt, then the reaction mixture was stirred at rtfor 2.5 hrs. On completion, the mixture was diluted with water (40 mL)and filtered, and the filter cake was diluted with ethyl acetate (20 mL)and washed with water (2×20 mL). Then the organic phase was concentratedin vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=432.1,tR=0.796. ¹H NMR (400 MHz, DMSO-d₆) δ=9.26 (s, 1H), 7.93 (br. s., 1H),7.83 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H),7.48-7.43 (m, 2H), 7.32 (br. s., 1H), 4.29-4.22 (m, 1H), 4.20-4.13 (m,1H), 3.96 (t, J=6.8 Hz, 2H), 3.90 (s, 3H), 2.83-2.74 (m, 1H), 2.35-2.29(m, 1H)

Step 4 (Example145)—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid

To a solution of(±)-N-[3-(4-carbamoylphenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-car-boxamide(230 mg, 532 umol) in methanol (20 mL) was added sodium hydroxide (4.00g in 25 mL water). Then the mixture was stirred at 90° C. for 16 hrs. Oncompletion, the mixture was cooled to rt and concentrated in vacuo toremove the methanol. Then water (20 mL) was added to the mixture and waswashed with ethyl acetate (40 mL). The aqueous phase was adjusted topH=3-4 with concentrated hydrochloric acid and filtered. The filter cakewas dissolved in methanol (10 mL) and water (20 mL) was added. Then thereaction mixture was lyophilized to give the title compound. LCMS: (ES⁺)m/z (M+H)⁺=433.0, tR=0.973 ¹H NMR (400 MHz, DMSO-d₆) δ=9.28 (s, 1H),7.89 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H),7.48-7.44 (m, 2H), 4.28-4.23 (m, 1H), 4.21-4.16 (m, 1H), 4.00-3.93 (m,2H), 3.91 (s, 3H), 2.79 (td, J=6.2, 12.7 Hz, 1H), 2.38-2.29 (m, 1H).

Example 146 &147—(S)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid &(R)-4-[(3)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-tetrahydrofuran-3-yl]benzoicacid

Compound of Example 145 was separated by SFC to give(S)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid and(R)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid. SFC (Condition: Base-MeOH, Column: OD (250 mm*30 mm, 10 um),Instrument: SFC-A).

Example 146 (peak 1):(S)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid or(R)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid: cSFC analytical tR: 3.708 min., ee: 98.3%; LCMS: (ES⁺) m/z(M+H)⁺=433.0, tR=0.967. ¹H NMR (400 MHz, DMSO-d₆) δ=9.28 (s, 1H), 7.89(d, J=8.0 Hz, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H),7.48-7.42 (m, 2H), 4.27 (d, J=8.8 Hz, 1H), 4.20 (d, J=8.8 Hz, 1H),3.99-3.93 (m, 2H), 3.90 (s, 3H), 2.79 (td, J=6.2, 12.7 Hz, 1H),2.35-2.30 (m, 1H).

Example 147 (peak 2):(R)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid or(S)-4-[(3)-3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid: cSFC analytical tR: 4.591 min., ee: 97.7%; LCMS: (ES⁺) m/z(M+H)⁺=433.0, tR=0.964. ¹H NMR (400 MHz, DMSO-d₆) δ=9.18 (s, 1H), 7.80(d, J=7.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.49-7.40 (m, 2H), 7.34 (d,J=8.0 Hz, 2H), 4.29 (d, J=9.0 Hz, 1H), 4.13 (d, J=9.0 Hz, 1H), 3.95 (t,J=7.0 Hz, 2H), 3.91 (s, 3H), 2.80 (td, J=6.0, 12.5 Hz, 1H), 2.37-2.29(m, 1H).

Example 148(±)-4,5-Dichloro-1-methyl-N-[3-[4-(1H-tetrazol-5-yl)phenyl]tetrahydro-furan-3-yl]indole-2-car-boxamide

4,5-dichloro-N-[3-(4-cyanophenyl)tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(95.0 mg, 229 umol, Example 143), sodium azide (17.8 mg, 275 umol) andammonium chloride (14.7 mg, 275 umol) were placed into a three neckflask under nitrogen. Then dimethyl formamide (2 mL) was added and thesolution was heated at 120° C. for 5 day under nitrogen. On completion,the reaction mixture was cooled to room temperature and poured intowater, and adjusted to pH=3-4 with hydrochloric acid solution (2N). Thenthe mixture was filtered. The filter cake was purified by prep-HPLC(condition: water (0.05% ammonia hydroxide v/v)-ACN; column: PhenomenexGemini C18 250*50 10 u) to give the title compound. LCMS: (ES⁺) m/z(M+1)⁺=457.1, tR=1.367. ¹H NMR (400 MHz, DMSO-d₆) δ=9.31 (s, 1H), 8.01(d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.60 (d, J=9.0 Hz, 1H),7.49-7.41 (m, 2H), 4.24 (q, J=9.1 Hz, 2H), 4.02-3.95 (m, 2H), 3.90 (s,3H), 2.81 (td, J=6.3, 12.7 Hz, 1H), 2.37 (td, J=7.9, 13.1 Hz, 1H).

Example149—(±)-2-[4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]aceticacid

Step 1—(±)-Ethyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetate

To a mixture of Xphos (61.1 mg, 128 umol), Pd₂(dba)₃ (58.6 mg, 64.0umol) and(±)-N-[3-(4-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide(300 mg, 640 umol, Example 142) in anhydrous tetrahydrofuran (4 mL) wasadded a solution of bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.5M) in anhydroustetrahydrofuran (10 mL) at rt and the reaction mixture was stirred at80° C. for 1 hr under nitrogen. On completion, the reaction mixture wasconcentrated in vacuo to give the crude product, which was purified bysilica gel chromatography (petroleum ether:ethyl acetate=5:1) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=475.1, tR=1.598. ¹H NMR (400MHz, CDCl₃) δ=7.49-7.42 (m, 2H), 7.40-7.38 (m, 1H), 7.36 (d, J=2.6 Hz,2H), 7.25-7.21 (m, 1H), 7.02 (s, 1H), 4.74 (d, J=10.0 Hz, 1H), 4.61-4.53(m, 1H), 4.22-4.18 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.99 (s, 3H), 3.66(s, 2H), 2.96-2.85 (m, 1H), 2.84-2.73 (m, 1H), 1.27 (t, J=7.2 Hz, 3H).

Step2—(±)-2-[4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]aceticacid

To a solution of (±)-ethyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetate(800 mg, 673 umol) in a mixture of tetrahydrofuran (10 mL) and water (10mL) was added lithium hydroxide (48.3 mg, 2.02 mmol) and the reactionmixture was stirred at rt for 16 hrs. On completion, the reactionmixture was concentrated in vacuo to remove tetrahydrofuran and theaqueous phase was acidified with 1N hydrochloric acid (5 mL) untilpH=3-4. The resulting mixture was filtrated and the filter cake waswashed with water (3×10 mL). The solid was dried in vacuo to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=448.8, tR=0.935. ¹H NMR (400 MHz,DMSO-d₆) δ=9.11 (br. s., 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz,1H), 7.39 (s, 1H), 7.31 (d, J=7.4 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 4.25(d, J=9.0 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 3.91 (d, J=7.0 Hz, 2H), 3.88(s, 3H), 3.30-3.23 (m, 2H), 2.81-2.69 (m, 1H), 2.36-2.26 (m, 1H).

Example 150 & 151(S)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-tetrahydrofuran-3-yl)phenyl)acetic acid and(R)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid

200 mg of(±)-2-[4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetic acid (Example 149) was separated by SFC (OD-3S_3_5_40_3ML Column:Chiralcel OD-3 100×4.6 mm I.D., 3 um. Mobile phase: methanol (0.05% DEA)in CO₂ from 5% to 40% Flow rate: 3 mL/min Wavelength: 220 nm) to givethe two enantiomers.(S)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid or(R)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid (Example 150, peak 1). cSFC analytical tR: 3.763min., ee: 100%; LCMS: (ES⁺) m/z (M+H)⁺=447.1, tR=0.846. ¹H NMR (400 MHz,DMSO-d₆) δ=9.14 (s, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H),7.41 (s, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 4.26 (d,J=9.2 Hz, 1H), 4.09 (d, J=9.0 Hz, 1H), 3.97-3.91 (m, 2H), 3.89 (s, 3H),3.32 (br. s., 2H), 2.82-2.73 (m, 1H), 2.34-2.24 (m, 1H).(R)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)-aceticacid or(S)-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid (Example 151, peak 2). cSFC analytical tR: 4.376min., ee: 97.2%; LCMS: (ES⁺) m/z (M+H)⁺=447.1, tR=0.869. ¹H NMR (400MHz, DMSO-d₆) δ=9.15 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.8 Hz,1H), 7.41 (s, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 4.26(d, J=9.0 Hz, 1H), 4.09 (d, J=9.2 Hz, 1H), 3.97-3.91 (m, 2H), 3.89 (s,3H), 3.34 (br. s., 2H), 2.77 (td, J=6.1, 12.6 Hz, 1H), 2.35-2.23 (m,1H).

Example152—(±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]propanoicacid

Step1—(±)-Ethyl-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]propanoate

A mixture of(±)-N-[3-(4-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide(700 mg, 1.50 mmol Example 142),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(43.4 mg, 75.0 umol), N,N-dimethylpyridin-4-amine (183 mg, 1.50 mmol)and allyl(chloro) palladium (13.7 mg, 75.0 umol) in xylene (20 mL) wasstirred at rt for 10 minutes under nitrogen. Then(3-ethoxy-2-methyl-3-oxo-propanoyl)oxypotassium (1.11 g, 6.00 mmol) wasadded in one portion and the reaction mixture was stirred at 130° C. for30 minutes. On completion, the reaction mixture was concentrated invacuo. The resulting solid was purified by silica gel chromatography(petroleum ether:ethyl acetate=3:1) to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=489.0, tR=1.695.

Step2—(±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]propanoicacid

To a solution of (±)-ethyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]propanoate(30.0 mg, 61.3 umol) in a mixture of tetrahydrofuran (4 mL) and water (4mL) was added lithium hydroxide (7.34 mg, 306 umol) and the reactionmixture was stirred at rt for 16 hours. On completion, the reactionmixture was concentrated in vacuo to removal tetrahydrofuran and theaqueous phase was acidified with 1 N hydrochloric acid (1 mL) untilpH=6. The solution was concentrated in vacuo. The resulting residue waspurified by prep-HPLC [water (10 mM NH₄HCO₃)-ACN, Phenomenex Gemini C18250*50 10 u] to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=461.0,tR=0.897. ¹H NMR (400 MHz, DMSO-d₆) δ=9.11 (s, 1H), 7.59 (d, J=8.9 Hz,1H), 7.44 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.22(d, J=8.4 Hz, 2H), 4.26 (d, J=9.0 Hz, 1H), 4.08 (dd, J=3.3, 9.0 Hz, 1H),3.96-3.89 (m, 5H), 3.25 (d, J=6.8 Hz, 1H), 2.77 (td, J=6.3, 12.5 Hz,1H), 2.34-2.26 (m, 1H), 1.22 (d, J=7.0 Hz, 3H).

Example153—(±)-2-[3-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]aceticacid

Step 1—(±)-Ethyl2-[3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetate

To a solution of(±)-N-[3-(3-bromophenyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide(300 mg, 640 umol, synthesized via Method 6, Step 1 with acid A andamine AC) in THE (2 mL) was added Pd₂(dba)₃ (58.6 mg, 64.0 umol) andXPhos (61.1 mg, 128 umol) at rt under nitrogen. Then a solution ofbromo-(2-ethoxy-2-oxo-ethyl) zinc (1.04 g, 4.49 mmol) in anhydroustetrahydrofuran (10 mL) was added, and the reaction mixture was stirredat 80° C. for 5 hours under nitrogen. The mixture was cooled to roomtemperature and water (50 mL) was added. Then the mixture was filtered.The filter cake was washed with dichloromethane (3×30 mL). The combinedorganic washings were concentrated to get the crude product. The crudewas purified by column chromatography (SiO₂, petroleum ether:ethylacetate=10:1 to 5:1) to get the title compound. ¹H NMR (300 MHz, CDCl₃)δ=7.37-7.28 (m, 3H), 7.22-7.09 (m, 3H), 6.99-6.91 (m, 1H), 6.76 (s, 1H),4.17-3.97 (m, 6H), 3.89 (s, 3H), 3.56 (s, 2H), 2.84-2.68 (m, 1H), 2.53(dt, J=12.90, 8.34 Hz, 1H), 1.13-1.19 (m, 3H).

Step2—(±)-2-[3-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]aceticacid

To a solution of (±)-ethyl2-[3-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]acetate(200 mg, 420 umol) in tetrahydrofuran (5 mL) and water (2 mL) was addedlithium hydroxide (30.2 mg, 1.26 mmol) and the mixture was stirred at rtfor 16 hours. To the mixture was added water (20 mL), then it was washedwith ethyl acetate (2×20 mL). Then the aqueous phase was adjusted topH=4-5 with aq. hydrochloric acid (2 N) and filtered. The filter cakewas triturated with dichloromethane to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=447.1, tR=0.854. ¹H NMR (400 MHz, DMSO-d6) δ=9.18 (s,1H), 7.60 (d, J=8.91 Hz, 1H), 7.45 (d, J=8.91 Hz, 1H), 7.39 (s, 1H),7.36-7.23 (m, 3H), 7.13 (d, J=7.15 Hz, 1H), 4.25 (d, J=9.16 Hz, 1H),4.12 (d, J=9.16 Hz, 1H), 3.98-3.92 (m, 2H), 3.90 (s, 3H), 3.54 (s, 2H),2.82-2.74 (m, 1H), 2.32-2.25 (m, 1H).

Example154—(±)-2-Cyano-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

Step 1—(±)-Methyl2-bromo-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate

To a solution of (±)-methyl4-(3-aminotetrahydrofuran-3-yl)-2-bromobenzoate (800 mg, 2.67 mmol) and4,5-dichloro-1-methyl-1H-indole-2-carboxylic acid (651 mg, 2.67 mmol) indichloromethane (15 mL) was added triethylamine (540 mg, 5.34 mmol) andHATU (1.12 g, 2.94 mmol). The mixture was stirred at rt for 12 hrs. Oncompletion, the reaction mixture was concentrated under vacuum to affordthe crude product which was purified by column chromatography (petroleumether:ethyl acetate=3:1) to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=9.33 (s, 1H), 7.78-7.74 (m, 2H), 7.62-7.59 (m, 2H), 7.48-7.44(m, 2H), 4.24-4.19 (m, 2H), 3.98-3.94 (m, 2H), 3.91 (s, 3H), 3.85 (s,3H), 2.76-2.74 (m, 1H), 2.36-2.34 (m, 1H).

Step 2—(±)-Methyl2-cyano-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate

To a solution of (±)-methyl2-bromo-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate (300 mg, 570 umol) in N,N-formamide (5 mL)was added Pd(PPh₃)₄ (65.8 mg, 57.0 umol) and dicyanozinc (200 mg, 1.71mmol). The mixture was flushed with nitrogen, stirred at 120° C. for 12hrs. On completion, the reaction mixture was concentrated under vacuumto afford the crude product, which was purified by prep-TLC (petroleumether:ethyl acetate=3:1) to afford the title compound.

Step 3—(±)-2-Cyano-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoic acid

To a solution of (±)-methyl2-cyano-4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate (94.2 mg, 0.2 mmol) in tetrahydrofuran(1.00 mL) and water (1.00 mL) was added lithium hydroxide (21 mg, 0.5mmol) at rt, and the resultant mixture was stirred for 16 hrs. Oncompletion, the mixture was concentrated in vacuo to remove thetetrahydrofuran. The aqueous phase was acidified with hydrochloridesolution (0.1 mL, 2N) to pH=5 at 0° C. A white solid precipitated; thesolid was filtered, and dried in vacuo to give the title compound. LCMS:(ES⁺) m/z (M+H)⁺=458.1, tR=0.692 ¹H NMR (400 MHz, DMSO-d₆) δ=9.29 (br.s, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.4 Hz, 1H),7.61 (d, J=9.2 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 4.24-4.18(m, 2H), 3.98-3.95 (m, 2H), 3.90 (s, 3H), 2.81-2.68 (m, 1H), 2.40-2.34(m, 1H).

Example 155—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-2-methyl-benzoicacid

Step 1—(±)-methyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-methyl-benzoate

A mixture of (±)-methyl2-bromo-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate(200 mg, 380 umol, synthesized from Step 1 as seen above in Example154), 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (47.7 mg, 380umol), cesium carbonate (247 mg, 760 umol) and Pd(dppf)Cl₂—CH₂Cl₂ (62.0mg, 76.0 umol) in water (1 mL) and dioxane (5 mL) was degassed andpurged with nitrogen gas 3 times, and then the mixture was stirred at100° C. for 4 hours under nitrogen gas atmosphere. On completion, thereaction mixture was concentrated in vacuo to get a residue. The residuewas purified by column chromatography (dichloromethane:ethylacetate=10:0 to 10:1) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=461.1, tR=0.941.

Step 2—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-methyl-benzoicacid

To a solution of (±)-methyl 4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-methyl-benzoate(120 mg, 260 umol) in water (2 mL) and tetrahydrofuran (8 mL) was addedlithium hydroxide (37.3 mg, 1.56 mmol). The mixture was stirred at 60°C. for 16 hours. On completion, the reaction mixture was concentrated invacuo to give a residue. The residue was acidified with 1 M hydrochloricacid to pH=3. Then the mixture was concentrated in vacuo to get thecrude product. The crude product was purified by prep-HPLC (Condition:water (0.1% TFA)-CAN; Column: Venusil XBP C₁₈ 150×25 mm×10 um) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=447.1, tR=0.865. ¹H NMR (400MHz, DMSO-d₆) δ=9.22 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.9 Hz,1H), 7.46 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.28 (br. s., 2H), 4.25-4.20(m, 1H), 4.19-4.11 (m, 1H), 3.98-3.92 (m, 2H), 3.91 (s, 3H), 2.81-2.72(m, 1H), 2.56-2.51 (m, 3H), 2.33-2.28 (m, 1H).

Example156—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]-2-ethyl-benzoicacid

Step 1—(±)-Methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-ethyl-benzoate

To a solution of methyl(±)-2-bromo-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate (100 mg, 190 umol, synthesized from Step 1as seen above in Example 154) and cesium carbonate (123 mg, 380 umol) intetrahydrofuran (2 mL) was added Pd(dppf)Cl₂ (13.9 mg, 19.0 umol) andtriethylborane (37.2 mg, 380 umol). The mixture was stirred at 60° C.for 16 hrs. On completion, the mixture was quenched with water (20 mL)and extracted with ethyl acetate (2×15 mL). The combined organic layerswere washed with brine and concentrated in vacuo. The residue waspurified by chromatography (petroleum ether:ethyl acetate=10:1 to 4:1)to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ=9.26 (s, 1H),7.75 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H),7.42 (s, 1H), 7.39 (d, J=1.51 Hz, 1H), 7.3-7.32 (m, 1H), 4.26-4.15 (m,2H), 4.01-3.93 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 2.89 (q, J=7.5 Hz,2H), 2.81-2.73 (m, 1H), 2.33 (dd, J=7.5, 5.4 Hz, 1H), 1.14 (t, J=7.4 Hz,3H).

Step2—(±)-4-[3-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-ethyl-benzoicacid

To a solution of (±)-methyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]-2-ethyl-benzoate (40.0 mg, 84.1 umol) intetrahydrofuran (4 mL) and water (2 mL) was added lithium hydroxide(16.1 mg, 673 umol). The mixture was stirred at rt for 32 hrs. Oncompletion, the mixture was concentrated to remove the organic solvent,the residue was diluted with water (20 mL), and extracted withdichloromethane (3×20 mL). The aqueous phase was acidified byhydrochloric acid (2 N) until pH=3-4. The aqueous phase was thenextracted with ethyl acetate (2×20 mL), dried and concentrated in vacuo.The residue was purified by Prep-HPLC (condition: water (0.225% FA)-ACNcolumn: Phenomenex Synergi C18 150*25*10 um) to give the title compound.LCMS: (ES⁺) m/z (M+H)⁺=461.0, tR=0.840. ¹H NMR (300 MHz, DMSO-d6) δ=9.24(s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.37-7.25 (m, 2H), 4.20 (q, J=9.2 Hz, 2H),3.99-3.93 (m, 2H), 3.90 (s, 3H), 2.91 (q, J=7.5 Hz, 2H), 2.81-2.74 (m,1H), 2.37-2.30 (m, 1H), 1.13 (t, J=7.3 Hz, 3H).

Example157—(±)-2-cyclopropyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid

Step 1—(±)-methyl2-cyclopropyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoate

To a solution of (±)-methyl2-bromo-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate (120 mg, 228 umol, synthesized from Step 1as seen above in Example 154) in toluene (5 mL) and water (1 mL) wasadded cyclopropylboronic acid (29.3 mg, 342 umol) and potassiumphosphate (145 mg, 684 umol). To the mixture was addedtetrakis(triphenylphosphine) palladium (0) (52.7 mg, 45.6 umol) undernitrogen atmosphere. The reaction was stirred at 100° C. for 24 hrsunder nitrogen. On completion, the mixture was concentrated in vacuo.The residue was purified by chromatography on silica gel (petroleumether:ethyl acetate=1:1 to dichloromethane:methanol=10:1) to give thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=487.1, tR=0.843.

Step2—(±)-2-cyclopropyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-tetrahydrofuran-3-yl]benzoicacid

To a solution of (±)-methyl2-cyclopropyl-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate (40.0 mg, 82.0 umol) in tetrahydrofuran (5mL) was added lithium hydroxide (15.7 mg, 656 umol) in water (500 uL)and methanol (1 mL), and the mixture was stirred at 60° C. for 3 hours.On completion, the mixture was adjusted to pH=4˜5 with HCl (4 M indioxane). The residue was purified by prep-HPLC (YMC-Actus ODS-AQ 150*305 u, water (0.1% TFA)-ACN) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=473.1, tR=0.844. ¹H NMR (400 MHz, DMSO-d₆) δ=12.79 (br. s., 1H),9.21 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.46 (d,J=8.8 Hz, 1H), 7.40 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 4.17(d, J=6.8 Hz, 2H), 3.94 (d, J=7.3 Hz, 2H), 3.90 (s, 3H), 2.68-2.77 (m,2H), 2.30 (t, J=6.6 Hz, 1H), 0.95 (d, J=8.5 Hz, 2H), 0.61 (t, J=7.4 Hz,2H).

Example158—(±)-2-[3-Cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydro-furan-3-yl]phenyl]aceticacid

Step1—(±)-3-Cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoylchloride

To a mixture of(±)-3-cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid (120 mg, 261 umol, synthesized via Method 6, Step 1 with acid A andamine AL) and a catalytic amount of N,N-dimethylformamide indichloromethane (10 mL) was added oxalyl chloride (66.4 mg, 523 umol)dropwise. The mixture was stirred at rt for 2 hrs. On completion, themixture was concentrated in vacuo to afford the title compound which wasused for next step directly.

Step2—(±)-4,5-Dichloro-N-[3-[2-cyano-4-(2-diazoethyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide

A solution containing potassium hydroxide (1.12 g, 19.9 mmol) in water(3 mL) and 2-(2-ethoxyethoxy)ethanol (6.54 g, 48.7 mmol) were placed inthe distillation flask. A solution containingN-4-dimethyl-N-nitroso-benzenesulfonamide (4.00 g, 18.7 mmol) in ether(30 mL) was placed in the addition funnel, meanwhile the receiving flaskwas cooled to 0° C. After heating the distillation flask to 70° C.,N-4-dimethyl-N-nitroso-benzenesulfonamide (4.00 g, 18.7 mmol) in ether(30 mL) was added dropwise over 0.5 hour. diazomethane (433 mg, 10.3mmol) in ether (30 mL) was collected as the distillate.

To a solution of(±)-3-cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]tetrahydrofuran-3-yl]benzoylchloride (120 mg, 251 umol) in dichloromethane (10 mL) was addeddropwise a solution of diazomethane (190 mg, 4.53 mmol) in ether (5 mL),and the mixture was stirred at rt for 16 hrs. On completion, dilutedacetic acid (5 mL) was added into the mixture, the mixture was basifiedwith sodium bicarbonate solution to pH=9, and extracted with ethylacetate (2×50 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuum to give a residue.The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=3:1) to afford the title compound. LCMS: (ES⁺) m/z(M+H)⁺=482.2, tR=0.879.

Step3—(±)-2-[3-Cyano-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]phenyl]aceticacid

To a mixture of(±)-4,5-dichloro-N-[3-[2-cyano-4-(2-diazoacetyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(45.0 mg, 93.3 umol) in tetrahydrofuran (4 mL) and water (0.4 mL) wasadded triethylamine (28.3 mg, 279 umol) and(2,2,2-trifluoroacetyl)oxysilver (20.6 mg, 93.3 umol). The mixture wasstirred at rt for 16 hrs. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified with prep-HPLC (Instrument: GX-D; Column: Boston Green ODS150*30 5 u; Mobile phase: 0.225% formic acid-acetonitrile) to afford thetitle compound. LCMS: (ES⁺) m/z (M+H)⁺=472.1, tR=0.786. ¹H NMR (400 MHz,DMSO-d6) δ=10.89 (br. s., 1H), 8.37 (s, 1H), 7.93 (s, 1H), 7.65 (d,J=8.9 Hz, 1H), 7.61 (s, 2H), 7.52-7.45 (m, 2H), 4.21-4.17 (m, 5H), 4.01(d, J=8.7 Hz, 1H), 3.84 (d, J=8.7 Hz, 1H), 3.69 (s, 2H), 2.59-2.55 (m,1H), 2.37 (t, J=7.6 Hz, 1H).

Example159—2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)-phenyl)aceticacid

Step 1—Ethyl 2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl) acetate

To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (156 mg,638 umol), HATU (259 mg, 680 umol), and triethylamine (129 mg, 1.28mmol) in methylene dichloride (10 mL) was added ethyl2-[4-(3-aminooxetan-3-yl)phenyl]acetate (100 mg, 425 umol) at rt. Thenthe reaction mixture was stirred at rt for 16 hours under nitrogen. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas diluted with ethyl acetate (30 mL), washed with aqueous hydrochloricacid (0.1N, 20 mL), followed by sat. sodium bicarbonate (20 mL), andbrine (30 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated in vacuo to give a crude product that was used as in innext step. LCMS: (ES⁺) m/z (M+H)⁺=461.1, tR=0.925.

Step2—2-(4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)oxetan-3-yl)phenyl)aceticacid

To a solution of ethyl2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]acetate (150 mg, 325 umol) in a mixture solvent of tetrahydrofuran (8mL) and water (2 mL) was added lithium hydroxide (54.6 mg, 1.30 mmol) inone portion at rt. The reaction mixture was stirred for 3 hours. Oncompletion, the mixture was concentrated in vacuo to give the crudeproduct. The crude product was purified by prep-HPLC (condition: water(0.05% ammonia hydroxide v/v-ACN; column: Phenomenex Gemini 150*25 mm*10um) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=431.0, tR=1.349.¹H NMR (400 MHz, DMSO-d₆) δ=9.75 (brs., 1H), 7.62 (d, J=8.8 Hz, 1H),7.46 (d, J=8.8 Hz, 1H), 7.43-7.41 (m, 3H), 7.23 (d, J=8.0 Hz, 1H), 5.04(d, J=6.8 Hz, 2H), 4.77 (d, J=6.4 Hz, 2H), 3.98 (s, 3H), 3.24 (s, 2H).

Example 160 & 161(S)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid &(R)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid

(±)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid (230 mg, Example 58) was purified by SFC (Condition: Base-TPA,Column: AS (250 mm*30 mm, 10 um) Instrument: SFC-A) to give twoenantiomers. Then the two enantiomers were purified by prep-HPLC(Condition: water (0.05% ammonia hydroxide v/v)-ACN; Column: PhenomenexGemini 150*25 mm*100 um):

(S)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid or(R)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid (Example 160) peak 1. cSFC analytical tR: 3.383 min., ee: 96%;LCMS: (ES⁺) m/z (M+H)⁺=447.0, tR=0.746. ¹HNMR (400 MHz, DMSO-d₆) δ=9.74(s, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.9Hz, 1H), 7.42 (s, 1H), 7.31 (d, J=8.3 Hz, 2H), 5.04 (d, J=6.8 Hz, 2H),4.79 (d, J=6.8 Hz, 2H), 3.97 (s, 3H), 3.60-3.58 (m, 1H), 1.33 (d, J=7.2Hz, 3H).

(R)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid or(S)-2-[4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]oxetan-3-yl]phenyl]propanoicacid (Example 161) peak 2. cSFC analytical tR: 3.571 min., ee: 92%;LCMS: (ES⁺) m/z (M+H)⁺=446.9, tR=0.743. ¹H NMR (400 MHz, DMSO-d₆) δ=9.73(s, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.52-7.45 (m, 3H), 7.41 (s, 1H), 7.32(d, J=8.3 Hz, 2H), 5.04 (d, J=6.7 Hz, 2H), 4.78 (d, J=6.5 Hz, 2H), 3.96(s, 3H), 3.51 (d, J=7.4 Hz, 1H), 1.32 (d, J=7.2 Hz, 3H).

Example162—(±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carbox-amido)tetrahydrofuran-3-yl)phenyl)aceticacid

Step 1—(±)-Ethyl4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoate

A solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (415 mg,1.70 mmol), diisopropylethylamine (659 mg, 5.10 mmol) and HATU (711 mg,1.87 mmol) in N,N-dimethylacetamide (4 mL) was stirred at rt for 1 hr.Then (±)-ethyl 4-(3-aminotetrahydro furan-3-yl)benzoate (400 mg, 1.70mmol) was added. The mixture was stirred at rt for 12 hrs. Oncompletion, the mixture was quenched with water (10 mL). The solid wascollected by filtration and washed with water (6 mL) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=461.0, tR=1.078.

Step2—(±)-4-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)benzoicacid

To a solution of (±)-ethyl4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoate (640 mg, 1.39 mmol) in tetrahydrofuran (12 mL) and water (4 mL)was added lithium hydroxide (100 mg, 4.17 mmol). The mixture was stirredat 60° C. for 12 hrs. On completion, the mixture was concentrated toremove the organic solvent, then acidified with hydrochloric acid (2 N)until pH=2. The solid was collected by filtration and washed with water(5 mL) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=433.0,tR=0.888.

Step 3—(±)-Methyl 4-(1-(hydroxyimino)ethyl)cyclohexanecarboxylate

To a solution of(±)-4-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]tetrahydrofuran-3-yl]benzoicacid (580 mg, 1.34 mmol) and diisopropylethylamine (519 mg, 4.02 mmol)in N,N-dimethylacetamide (4 mL) was added HATU (600 mg, 1.47 mmol). Themixture was stirred at rt for 1 hr, then N-methoxymethanamine (144 mg,1.47 mmol) was added. The mixture was stirred at rt for 2 hrs. Oncompletion, the mixture was quenched with water (10 mL). The solid wascollected by filtration and washed with water (10 mL) to give the titlecompound. LCMS: (ES⁺) m/z (M+H)⁺=476.0, tR=0.903.

Step4—(±)-4,5-Dichloro-N-(3-(4-(cyclopropanecarbonyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide

To a solution of(±)-4,5-dichloro-N-[3-[4-[methoxy(methyl)carbamoyl]phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(500 mg, 1.05 mmol) in tetrahydrofuran (10 mL) was addedbromo(cyclopropyl)magnesium (1.2 M, 1.75 mL). The mixture was stirred atrt for 1 hr. On completion, the mixture was quenched with water (10 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by chromatography (dichloromethane:ethylacetate=15:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=457.0,tR=1.056. ¹H NMR (400 MHz, DMSO-d₆) δ=9.32 (s, 1H), 8.03 (d, J=8.3 Hz,2H), 7.61 (d, J=8.0 Hz, 3H), 7.49-7.44 (m, 2H), 4.29-4.18 (m, 2H),4.02-3.95 (m, 2H), 3.91 (s, 3H), 2.36-2.29 (m, 1H), 1.06-0.98 (m, 4H).

Step5—(±)-4,5-Dichloro-N-(3-(4-(1-cyclopropyl-2-methoxyvinyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide

To the suspension of methoxymethyl(triphenyl)phosphonium chloride (225mg, 656 umol) in tetrahydrofuran (2 mL) was added n-butyllithium (2.5 M,276 uL) at 0° C. The mixture was stirred at 0° C. for 0.5 hr, then(±)-4,5-dichloro-N-[3-[4-(cyclopropanecarbonyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(150 mg, 328 umol) was added. The mixture was stirred at rt for 12 hrs.On completion, the mixture was quenched with water (5 mL) and extractedwith ethyl acetate (3×10 mL). The combined organic layers were driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography (petroleum ether:ethyl acetate=4:1) to givethe title compound. LCMS: (ES⁺) m/z (M+H)⁺=485.1, tR=1.208.

Step6—(±)-4,5-Dichloro-N-(3-(4-(1-cyclopropyl-2-oxoethyl)phenyl)tetrahydrofuran-3-yl)-1-methyl-1H-indole-2-carboxamide

A mixture of(±)-4,5-dichloro-N-[3-[4-[(E)-1-cyclopropyl-2-methoxy-vinyl]phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(80.0 mg, 165 umol) in formic acid (79.2 mg, 1.65 mmol) was stirred atrt for 8 hrs. On completion, the mixture was quenched with water (5 mL).The solid was collected by filtration and washed with water (5 mL) togive the title compound. LCMS: (ES⁺) m/z (M+H)⁺=471.1, tR=1.042.

Step7—(±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)aceticacid

To a solution of(±)-4,5-dichloro-N-[3-[4-(1-cyclopropyl-2-oxo-ethyl)phenyl]tetrahydrofuran-3-yl]-1-methyl-indole-2-carboxamide(40.0 mg, 84.9 umol) in tert-butanol (2 mL) was added 2-methylbut-2-ene(59.5 mg, 849 umol), aqueous sodium dihydrogen phosphate (0.85 M, 499uL) and aqueous sodium chlorite (0.51 M, 499 uL). The mixture wasstirred at rt for 1 hr. On completion, the mixture was diluted withwater (5 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by prep-HPLC (column: YMC-ActusODS-AQ 150*30 5 u; mobile phase: [water (0.1% TFA)-ACN]; ACN %: 45%-75%,11 min) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺=487.1,tR=0.904. ¹H NMR (400 MHz, DMSO-d₆) δ=12.34 (br. s., 1H), 9.18 (s, 1H),7.61 (d, J=8.8 Hz, 1H), 7.49-7.43 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.29(m, 2H), 4.27 (d, J=9.3 Hz, 1H), 4.12 (d, J=9.0 Hz, 1H), 3.99-3.93 (m,2H), 3.92 (s, 3H), 2.85-2.71 (m, 2H), 2.35-2.29 (m, 1H), 1.33 (br. s.,1H), 0.63-0.54 (m, 1H), 0.48-0.39 (m, 1H), 0.35-0.26 (m, 1H), 0.14 (m,1H).

Example163—(±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-6-methoxy-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid

(±)-2-Cyclopropyl-2-(4-(3-(4,5-dichloro-6-methoxy-1-methyl-1H-indole-2-carboxamido)tetrahydrofuran-3-yl)phenyl)acetic acid was made in the same method asExample 162, starting with acid F and amine AN in the first step. In thefinal step, the residue was purified by prep-HPLC (column: WatersXbridge 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; ACN %: 15%-45%, 10 min) to give the title compound. LCMS(ES⁺): 517.0 m/z (M+H)⁺, tR=0.767 min. ¹H NMR (400 MHz, DMSO-d₆) δ=9.0.2(s, 1H), 7.38 (d, J=7.6 Hz, 3H), 7.34-7.28 (m, 2H), 7.25 (s, 1H), 4.26(d, J=9.2 Hz, 1H), 4.11 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.92 (br s,2H), 3.90 (s, 3H), 2.80-2.75 (m, 1H), 2.66 (d, J=10.4 Hz, 1H), 2.31-2.28(m, 1H), 1.35-1.30 (m, 1H), 0.54-0.52 (m, 1H), 0.39-0.38 (m, 1H),0.28-0.27 (m, 1H), 0.09-0.06 (m, 1H).

Example 164—4-Chloro-5-methoxy-1-methyl-N-(3-(4-(N-propionylsulfamoyl)phenyl)-oxetan-3-yl)-1H-indole-2-carboxamide

To a solution of N-[4-(3-aminooxetan-3-yl)phenyl]sulfonylpropanamide(140 mg, 492 umol) and 4-chloro-5-methoxy-1-methyl-indole-2-carboxylicacid (118 mg, 492 umol) in N,N-dimethylformamide (15 mL) was added HATU(374 mg, 984 umol) and triethylamine (149 mg, 1.48 mmol, 204 uL). Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas dissolved in dichloromethane (10 mL) and washed with 1N citric acid(5 mL) until pH=3-4. The organic layer was dried over anhydrous sodiumsulfate, filtrated and concentrated in vacuo. The residue was purifiedby prep-HPLC (Instrument: LC-L; Condition: water (0.225% FA)-ACN;Column: Phenomenex Synergi C18 150*30 mm*4 um) to afford to afford thetitle product (63.1 mg, 25% yield) as white solid. LCMS: (ES⁺) m/z(M+H)⁺=506.1, tR=0.804. ¹H NMR (400 MHz, DMSO-d₆) δ=9.76 (s, 1H), 7.95(d, J=8.3 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H), 7.59-7.49 (d, J=9.0 Hz, 1H),7.35 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 5.07 (d, J=6.8 Hz, 2H), 4.81 (d,J=6.8 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 2.20 (q, J=7.5 Hz, 2H), 0.89(t, J=7.5 Hz, 3H).

Example165—4-Chloro-5-methoxy-1-methyl-N-(3-(4-((methylsulfonyl)carbamoyl)-phenyl)oxetan-3-yl)-1H-indole-2-carboxamide

To a solution of 4-(3-aminooxetan-3-yl)-N-methylsulfonyl-benzamide (133mg, 492 umol) and 4-chloro-5-methoxy-1-methyl-indole-2-carboxylic acid(118 mg, 492 umol) in N,N-dimethylformamide (8 mL) was added HATU (374mg, 984 umol) and triethylamine (149 mg, 1.48 mmol). The reactionmixture was stirred at rt for 16 hrs under nitrogen. The reactionmixture was concentrated in vacuo. The residue was dissolved indichloromethane (10 mL) and washed with 1N citric acid (5 mL) untilpH=3-4. The organic layer was dried over anhydrous sodium sulfate,filtrated and concentrated in vacuo. The residue was purified bypre-HPLC (Instrument: GX-C; Condition: water (0.225% FA)-ACN; Column:Boston Green ODS 150*30 5 u) to give the title compound. LCMS: (ES⁺) m/z(M+H)⁺=492.2, tR=0.804. ¹H NMR (400 MHz, DMSO-d₆) δ=12.18 (br. s., 1H),9.75 (s, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.3 Hz, 2H), 7.54 (d,J=9.0 Hz, 1H), 7.33 (s, 1H), 7.26 (d, J=9.3 Hz, 1H), 5.07 (d, J=6.8 Hz,2H), 4.81 (d, J=6.8 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.34 (s, 3H).

Example 166: 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase CoupledAssay

Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorasecoupled assay (500 uM NAD)

PHGDH activity was determined by detecting the NADH produced during thereaction. Diaphorase was used to catalyze the oxidation of NADH with theconcomitant reduction of resazurin to the fluorescent product resorufin.Resorufin fluorescence quantitatively reflected the production of NADHby the PHGDH reaction. To drive the forward reaction, two enzymes in theserine synthesis pathway subsequent to PHGDH, Phosphoserineaminotransferase (PSAT1) and phosphoserine phosphatase (PSPH) were alsoadded to the reaction.

Briefly, serial dilution of compounds were incubated in a volume of 20μL in 384 well plates with the assay mixture containing 5 nM PHGDH, 500nM PSAT1, 500 nM PSPH, 500 μM NAD⁺, 80 uM 3-phosphoglycerate, 1 mMglutamate, 57 uM Resazurin and 0.2 mg/ml Diaphorase in assay buffercontaining 50 mM Trisethanoloamine (TEA) pH8.0, 10 mM MgCl₂, 0.01%Tween-20 and 0.05% Bovine Serum Albumin (BSA). The plate was thenincubated at 30° C. for 60 minutes and resorufin fluorescence wasmeasured at emission wavelength 598 nm following excitation at 525 nm.The positive control consisted of the complete reaction mixture with 4%DMSO and was set to 0% inhibition. The negative control consisted of thereaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition.Percent inhibition with the compounds was then calculated by normalizingthe fluorescence observed at a given compound concentration to thepositive and negative controls. IC₅₀ was calculated by plotting the %inhibition versus concentration and using hyperbolic fit to determinecompound concentration corresponding to 50% inhibition.

Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorasecoupled assay (20 uM NAD)

Serial dilution of compounds were incubated in a volume of 20 μL in 384well plates with the assay mixture containing 10 nM PHGDH, 500 nM PSAT1,500 nM PSPH, 20 μM NAD, 80 uM 3-phosphoglycerate, 1 mM glutamate, 57 uMResazurin and 0.2 mg/ml Diaphorase in assay buffer containing 50 mMTrisethanoloamine (TEA) pH8.0, 10 mM MgCl₂, 0.01% Tween-20 and 0.05%Bovine Serum Albumin (BSA). The plate was then incubated at 30° C. for60 minutes and resorufin fluorescence was measured at emissionwavelength 598 nm following excitation at 525 nm. The positive controlconsisted of the complete reaction mixture with 4% DMSO and was set to0% inhibition. The negative control consisted of the reaction mixlacking PHGDH with 400 DMSO and was set to 10000 inhibition. Percentinhibition with the compounds was then calculated by normalizing thefluorescence observed at a given compound concentration to the positiveand negative controls. IC₅₀ was calculated by plotting the 0 inhibitionversus concentration and using hyperbolic fit to determine compoundconcentration corresponding to 5000 inhibition.

Assay Results

Table 2 shows the activity of selected compounds of this invention inthe full-length PHGDH activity inhibition assay. The compound numberscorrespond to the compound numbers in Table 1 and Experimental numbers(“e” numbers), above. Compounds having an activity designated as “A”provided an IC₅₀ of 0.001-1 μM; compounds having an activity designatedas “B” provided an IC₅₀ of 1-5 μM; compounds having an activitydesignated as “C” provided an IC₅₀ of 5-10 μM and compounds having anactivity designated as “D” provided an IC₅₀>10 μM. “NA” stands for “notassayed.”

TABLE 2 PHGDH Activity Inhibition Data FL FL Compound/ DiaphoraseDiaphorase Experimental 500 μM 20 μM # NAD NAD I-1 e3 A NA I-2 e125 A NAI-3 e124 A NA I-4 e123 A NA I-5 or I-6 A NA e132 peak 2 I-6 or I-5 A NAe131 peak 1 I-7 e117 A NA I-8 e116 A NA I-9 e137 A NA I-10e120 A NA I-11e72 A NA I-12 e86 A NA I-13 e111 A NA I-14 e113 A NA I-15 e162 A NA I-16e87 A NA I-17 e85 A NA I-18 e84 A NA I-19 e94 A NA I-20 e83 A NA I-21e127 A NA I-22 e118 A NA I-23 e82 A NA I-24 e114 A NA I-25 e136 A NAI-26 e130 A NA I-27 e110 A NA I-28 e108 A NA I-29 e135 A NA I-30 e134 ANA I-31 e112 A NA I-32 e64 A NA I-33 e62 A NA I-34 or I-35 A NA e161peak 2 I-35 or I-34 A NA e160 peak 1 I-36 e107 A NA I-37 e109 A NA I-38e115 A NA I-39 e81 A NA I-40 e55 A NA I-41 e92 A NA I-42 e133 A NA I-43e126 A NA I-44 e76 A NA I-45 e74 A NA I-46 e73 A NA I-47 e77 A NA I-48e71 A NA I-49 e60 A NA I-50 e75 A NA I-51 e68 A NA I-52 e91 A NA I-53e80 A NA I-54 e79 A NA I-55 e54 A NA I-56 e78 A NA I-57 e53 A NA I-58e70 A NA I-59 e38 A NA I-60 e65 A NA I-61 e47 A NA I-62 e46 A NA I-63e44 A NA I-64 e57 A NA I-65 e69 A NA I-66 e67 A NA I-67 e59 A NA I-68e58 A NA I-69 e52 C NA I-70 e61 A NA I-71 e158 B NA I-72 e56 A NA I-73e28 B NA I-74 e27 A NA I-75 e66 A NA I-76 e42 A NA I-77 e63 A NA I-78e40 A NA I-79 e41 A NA I-80 e103 A NA I-81 e105 A NA I-82 e51 A NA I-83e50 A NA I-84 e49 A NA I-85 e48 A NA I-86 e45 A NA I-87 e37 A NA I-88e156 B NA I-89 e104 B NA I-90 e43 A NA I-91 e90 A NA I-92 e101 A NA I-93e106 A NA I-94 e98 A NA I-95 e96 B NA I-96 e36 A NA I-97 e102 A NA I-98e155 A NA I-99 e89 A NA I-100 e99 A NA I-101 e157 B NA I-102 e100 A NAFL FL Diaphorase Diaphorase Compound/ 500 μM 20 μM #(I-X) NAD NAD I-103e39 A NA I-104 e97 A NA I-105 e152 A NA I-106 e31 B NA I-107 e24 A NAI-108 or A NA I-109 e151 peak 2 I-109 or A NA I-108 e150 peak 1 I-110e20 A NA I-111 e95 A NA I-112 e159 A NA I-113 e35 A NA I-114 e34 B NAI-115 e33 A NA I-116 e32 A NA I-117 e30 B NA I-118 e29 A NA I-119 e153 ANA I-120 e154 A NA I-121 e21 B NA I-122 e26 A NA I-123 e23 A NA I-124e25 B NA I-125 e19 B NA I-126 e18 C NA I-127 e22 — A I-128 e148 — AI-129 e149 — A I-130 e17 — A I-131 e144 — B I-132 or NA A I-133 e147peak 2 I-133 or — A I-132 e146 peak 1 I-134 e143 NA B I-135 e142 NA BI-136 e145 — A I-137 e141 NA A I-138 e16 NA C I-139 e14 — B I-140 e15 NAA I-141 e140 NA B I-142 e7 NA C I-143 e139 NA B I-144 e11 NA A I-145 e13NA C I-146 e6 NA C I-147 e8 NA B I-148 e9 NA C I-149 e12 NA C I-150 e5NA C I-151 e10 NA B I-152 e3 NA B I-153 e2 NA C I-154 e4 NA C I-155 e1NA C I-156 e119 A NA I-157 or A NA I-158 e128 peak 1 I-158 or A NA I-157e129 peak 2 I-159 e121 A NA I-160 e138 A NA I-161 e164 A NA I-162 e165 ANA I-163 e163 A NA I-164 e88 A NA I-165 e120 A NA

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₁₋₄alkyl; each of R² and R³ is independently halogen, —OR, —CN, C₁₋₆aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R′; orR² and R³ are optionally taken together with the carbon atoms to whichthey are attached and any intervening atoms to form a 5-8 memberedpartially unsaturated ring having 0-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; R⁴ is hydrogen, halogen, —OR⁵, —CN,C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 halogens, or-L-R′; each R is independently hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, a 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R⁵ is hydrogen,—(CH₂)_(n)-phenyl, —(CH₂)_(n)-Cy′, or C₁₋₆ alkyl optionally substitutedwith 1, 2, or 3 halogens; each L is independently a C₁₋₆ bivalentstraight or branched hydrocarbon chain wherein 1-4 methylene units ofthe chain are independently and optionally replaced with —O—, —C(O)—,—C(O)O—, —OC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —C(O)N(R)—, —(R)NC(O)—,—N(R)—, —N(R)C(O)N(R)—, —S—, —SO—, or —SO₂—; each R′ is independentlyhydrogen, C₁₋₆ aliphatic, or an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R⁶ is hydrogen or C₁₋₄ alkyl; R⁷ is hydrogen, —CO₂R, optionallysubstituted C₁₋₆ aliphatic, -Cy-, or a bivalent 3-7 membered ring; L¹ isa covalent bond or a C₁₋₈ bivalent straight or branched hydrocarbonchain wherein 1-5 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—,—C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—,—SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,—(R)NC(S)—, —(R)NC(S)N(R)—, or -Cy-; each -Cy- is independently abivalent 6-membered arylene ring containing 0-2 nitrogen atoms, or abivalent 5-membered heteroarylene ring with 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a bivalentpartially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein -Cy- is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkyl or —OR; -Cy′ is a 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur,R¹⁰ is C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 halogens,—C(O)CH₃, or —SO₂—N(R¹)(R¹¹); R¹¹ is —C(O)CH₃, —C(O)NHR¹, or pyrazinyl;n is independently 0, 1, 2, 3, 4, or 5; m is independently 1, or 2; X isO, S, or —N(R¹⁰)—; and each of Y¹ and Y² is independently ═N— or═C(R⁴)—.
 2. The compound according to claim 1, wherein R¹ is methyl. 3.The compound according to claim 2, wherein R² is halogen, —OR, —CN, or-L-R′.
 4. The compound according to claim 2, wherein R² is F, Cl, —CF₃,—OCF₃, —OCHF₂, —OCH₂Ph, —OCH₃,


5. The compound according to claim 2, wherein R³ is halogen or —OR. 6.The compound according to claim 3, wherein both of R² and R³ arehalogen.
 7. The compound according to claim 6, wherein R⁴ is hydrogen.8. The compound according to claim 2, wherein L¹ is SO₂NH—,


9. The compound according to claim 8, wherein L¹ is

10-16. (canceled)
 17. The compound according to claim 1, wherein saidcompound is any of Formulae III-a, III-b, III-c, III-d, III-e, III-f,III-g, III-h, or III-i:

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adjuvant, carrier, or vehicle.
 20. (canceled)
 21. A methodfor treating cancer in a patient in need thereof, comprisingadministering to said patient the compound of claim 1, wherein thecancer is melanoma or breast cancer.
 22. (canceled)
 23. A method fortreating a tumor in a patient in need thereof, comprising administeringto said patient the compound of claim 1, wherein the tumor comprises amelanoma, breast, or lung cancer.
 24. (canceled)
 25. The method of claim23, wherein the tumor comprises a small cell lung cancer (SCLC) or anon-small cell lung cancer (NSCLC).
 26. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition comprising a compound according to any one of claim 26 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adjuvant, carrier, or vehicle.
 28. A method for treatingcancer in a patient in need thereof, comprising administering to saidpatient the compound of claim 26, wherein the cancer is melanoma orbreast cancer.
 29. A method for treating a tumor in a patient in needthereof, comprising administering to said patient the compound of claim26, wherein the tumor comprises a melanoma, breast, or lung cancer. 30.The method of claim 29, wherein the tumor comprises a small cell lungcancer (SCLC) or a non-small cell lung cancer (NSCLC).